Growth-hormone secretagogues

ABSTRACT

This invention is directed to compounds of the formula                    
     and the pharmaceutically-acceptable salts thereof, where the substituents are as defined in the Specification, which are growth hormone secretogogues and which increase the level of endogenous growth hormone. The compounds of this invention are useful for the treatment and prevention of osteoporosis, congestive heart failure, frailty associated with aging, obesity; accelerating bone fracture repair, attenuating protein catabolic response after a major operation, reducing cachexia and protein loss due to chronic illness, accelerating wound healing, or accelerating the recovery of burn patients or patients having undergone major surgery; improving muscle strength, mobility, maintanence of skin thickness, metabolic homeostasis or renal homeostasis. The compounds of the present invention are also useful in treating osteoporosis when used in combination with: a bisphosphonate compound such as alendronate; estrogen, premarin, and optionally progesterone, an estrogen agonist or antagonist; or calcitonin, and pharmaceutical compositions useful therefor. Further, the present invention is directed to pharmaceutical composition useful for increasing the endogenous production or release of growth hormone in a human or other animal which comprises an effective amount of a compound of the present invention and a growth hormone secretagogue selected from GHRP-6, Hexarelin, GHRP-1, growth hormone releasing factor (GRF), IGF-1, IGF-2 or B-HT920. The invention is also directed to intermediates useful in the preparation of compounds of formula I.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. application Ser. No. 09/259,776,filed Mar. 1, 1999, U.S. Pat. No. 6,124,264 entitled Growth-HormoneSecretagogues”, which is a further division of U.S. application Ser. No.09/068,566, filed May 21, 1998, which is the national stage under 35U.S.C. §371(c) of International Patent Application No. PCT/IB96/01353,filed Dec. 4, 1996, claiming priority to U.S. Provisional ApplicationSer. No. 60/009,469, filed Dec. 28, 1995.

This invention relates to dipeptide compounds which are growth hormonesecretagogues and are useful for the treatment and prevention ofosteoporosis.

BACKGROUND OF THE INVENTION

Growth hormone (GH), which is secreted from the pituitary gland,stimulates growth of all tissues of the body that are capable ofgrowing. In addition, growth hormone is known to have the followingbasic effects on the metabolic process of the body:

1. Increased rate of protein synthesis in substantially all cells of thebody;

2. Decreased rate of carbohydrate utilization in cells of the body;

3. Increased mobilization of free fatty acids and use of fatty acids forenergy.

Deficiency in growth hormone results in a variety of medical disorders.In children, it causes dwarfism. In adults, the consequences of acquiredGH deficiency include profound reduction in lean body mass andconcomitant increase in total body fat, particularly in the truncalregion. Decreased skeletal and cardiac muscle mass and muscle strengthlead to a significant reduction in exercise capacity. Bone density isalso reduced. Administration of exogenous growth hormone has been shownto reverse many of the metabolic changes. Additional benefits of therapyhave included reduction in LDL cholesterol and improved psychologicalwell-being.

In cases where increased levels of growth hormone were desired, theproblem was generally solved by providing exogenous growth hormone or byadministering an agent which stimulated growth hormone production and/orrelease. In either case the peptidyl nature of the compound necessitatedthat it be administered by injection. Initially the source of growthhormone was the extraction of the pituitary glands of cadavers. Thisresulted in an expensive product, and carried with it the risk that adisease associated with the source of the pituitary gland could betransmitted to the recipient of the growth hormone (e.g.,Jacob-Cruetzfeld disease). Recently, recombinant growth hormone hasbecome available which, while no longer carrying any risk of diseasetransmission, is still a very expensive product which must be given byinjection or by a nasal spray.

Most GH deficiencies are caused by defects in GH release, not primarydefects in pituitary synthesis of GH. Therefore, an alternative strategyfor normalizing serum GH levels is by stimulating its release fromsomatotrophs. Increasing GH secretion can be achieved by stimulating orinhibiting various neurotransmitter systems in the brain andhypothalamus. As a result, the development of synthetic growthhormone-releasing agents to stimulate pituitary GH secretion are beingpursued, and may have several advantages over expensive and inconvenientGH replacement therapy. By acting along physiologic regulatory pathways,the most desirable agents would stimulate pulsatile GH secretion, andexcessive levels of GH that have been associated with the undesirableside effects of exogenous GH administration would be avoided by virtueof intact negative feedback loops.

Physiologic and pharmacologic stimulators of GH secretion includearginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin,and insulin induced hypoglycemia, as well as activities such as sleepand exercise, indirectly cause growth hormone to be released from thepituitary by acting in some fashion on the hypothalamus perhaps eitherto decrease somatostatin secretion or to increase the secretion of theknown secretagogue growth hormone releasing factor (GHRF) or an unknownendogenous growth hormone-releasing hormone or all of these.

Other compounds have been developed which stimulate the release ofendogenous growth hormone such as analogous peptidyl compounds relatedto GRF or the peptides of U.S. Pat. No. 4,411,890. These peptides, whileconsiderably smaller than growth hormones are still susceptible tovarious proteases. As with most peptides, their potential for oralbioavailability is low. WO 94/13696 refers to certain spiropiperidinesand homologues which promote release of growth hormone. Preferredcompounds are of the general structure shown below.

WO 94/11012 refers to certain dipeptides that promote release of growthhormone. These dipeptides have the general structure

where L is

The compounds of WO 94/11012 and WO 94/13696 are reported to be usefulin the treatment of osteoporosis in combination with parathyroid hormoneor a bisphosphonate.

SUMMARY OF THE INVENTION

This invention provides compounds of the formula:

the racemic-diastereomeric mixtures and optical isomers of saidcompounds and the pharmaceutically-acceptable salts and prodrugsthereof, wherein

e is 0 or 1;

n and w are each independently 0, 1 or 2, provided that w and n cannotboth be 0 at the same time;

Y is oxygen or sulfur;

R¹ is hydrogen, —CN, —(CH₂)_(q)N(X⁶)C(O)X⁶,—(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)SO₂(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)SO₂X⁶, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)C(O)OX⁶,—(CH₂)_(q)C(O)O(CH₂)_(t)—A¹, —(CH₂)_(q)OX⁶, —(CH₂)_(q)OC(O)X⁶,—(CH₂)_(q)OC(O)(CH₂)_(t)—A¹, —(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)OX⁶, —(CH₂)_(q)N(X⁶)SO₂N(X⁶)(X⁶),—(CH₂)_(q)S(O)_(m)X⁶, —(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹, —(C₁-C₁₀)alkyl,—(CH₂)_(t)—A¹, —(CH₂)_(q)—(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹—(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)—(C₃-C₇)cycloalkyl;

where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxyl, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl or 1, 2 or 3 fluoro; Y¹ is O, S(O)_(m), —C(O)NX⁶—,—CH═CH—, —N(X⁸)C(O)—, —C(O)NX⁶—, —C(O)O—, —OC(O)N(X⁸)— or —OC(O)—;

q is 0, 1, 2, 3 or 4;

t is 0, 1, 2 or 3;

said (CH₂)_(q) group and (CH₂)_(t) group may each be optionallysubstituted with hydroxyl, (C₁-C₄)alkoxy, carboxyl, —CONH₂,—S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or3 fluoro, or 1 or 2 (C₁-C₄)alkyl;

R² is hydrogen, (C₁-C₈)alkyl, —(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl,—(C₁-C₄)alkyl-A¹ or A¹; where the alkyl groups and the cycloalkyl groupsin the definition of R² are optionally substituted with hydroxyl,—C(O)OX⁶, —C(O)N(X⁶)(X⁶), —N(X⁶)(X⁶), —S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹,—C(O)(X⁶), CF₃, CN or 1, 2 or 3 halogen;

R³ is A¹, (C₁-C₁₀)alkyl, —(C₁-C₆)alkyl—A¹,—(C₁-C₈)alkyl-(C₃-C₇)cycloalkyl, —(C₁-C₅)alkyl-X¹—(C₁-C₅)alkyl,—(C₁-C₅)alkyl-X¹—(C₀-C₅)alkyl-A¹ or—(C₁-C₅)alkyl-X¹—(C₁-C₅)alkyl-(C₃-C₇)cycloalkyl;

where the alkyl groups in the definition of R³ are optionallysubstituted with —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1, 2, 3, 4 or 5halogens, or 1, 2 or 3 OX³; X¹ is O, S(O)_(m), —N(X²)C(O)—, —C(O)N(X²)—,—OC(O)—, —C(O)O—, —CX²═CX²—, —N(X²)C(O)O—, —OC(O)N(X²)— or —C═C—;

R⁴ is hydrogen, (C₁-C₆)alkyl or (C₃-C₇)cycloalkyl, or R⁴ is takentogether with R³ and the carbon atom to which they are attached and form(C₅-C₇)cycloalkyl, (C₅-C₇)cycloalkenyl, a partially saturated or fullysaturated 4- to 8-membered ring having 1 to 4 heteroatoms independentlyselected from the group consisting of oxygen, sulfur and nitrogen, or isa bicyclic ring system consisting of a partially saturated or fullysaturated 5- or 6-membered ring, fused to a partially saturated, fullyunsaturated or fully saturated 5- or 6-membered ring, optionally having1 to 4 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen;

X⁴ is hydrogen or (C₁-C₆)alkyl or X⁴ is taken together with R⁴ and thenitrogen atom to which X⁴ is attached and the carbon atom to which R⁴ isattached and form a five to seven membered ring;

R⁶ is a bond or is

where a and b are independently 0, 1, 2 or 3;

X⁵ and X^(5a) are each independently selected from the group consistingof hydrogen, trifluoromethyl, A¹ and optionally substituted(C₁-C₆)alkyl;

the optionally substituted (C₁-C₆)alkyl in the definition of X⁵ andX^(5a) is optionally substituted with a substituent selected from thegroup consisting of A¹, OX², —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX²,(C₃-C₇)cycloalkyl, —N(X²)(X²) and —C(O)N(X²)(X²);

or the carbon bearing X⁵ and X^(5a) forms one or two alkylene bridgeswith the nitrogen atom bearing R⁷ and R⁸ wherein each alkylene bridgecontains 1 to 5 carbon atoms, provided that when one alkylene bridge isformed then X⁵ or X^(5a) but not both may be on the carbon atom and R⁷or R⁸ but not both may be on the nitrogen atom and further provided thatwhen two alkylene bridges are formed then X⁵ and X^(5a) cannot be on thecarbon atom and R⁷ and R⁸ cannot be on the nitrogen atom;

or X⁵ is taken together with X^(5a) and the carbon atom to which theyare attached and form a partially saturated or fully saturated 3- to7-membered ring, or a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen;

or X⁵ is taken together with X^(5a) and the carbon atom to which theyare attached and form a bicyclic ring system consisting of a partiallysaturated or fully saturated 5- or 6-membered ring, optionally having 1or 2 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen, fused to a partially saturated, fullysaturated or fully unsaturated 5- or 6-membered ring, optionally having1 to 4 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen;

Z¹ is a bond, O or N—X², provided that when a and b are both 0 then Z¹is not N—X² or O;

R⁷ and R⁸ are independently hydrogen or optionally substituted(C₁-C₆)alkyl;

where the optionally substituted (C₁-C₆)alkyl in the definition of R⁷and R⁸ is optionally independently substituted with A¹,—C(O)O—(C₁-C₆)alkyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1 to 3hydroxy, 1 to 3 —O—C(O)(C₁-C₁₀)alkyl or 1 to 3 (C₁-C₆)alkoxy; or

R⁷ and R⁸ can be taken together to form —(CH₂)_(r)—L—(CH₂)_(r)—;

where L is C(X²)(X²), S(O)_(m) or N(X²);

A¹ for each occurrence is independently (C₅-C₇)cycloalkenyl, phenyl or apartially saturated, fully saturated or fully unsaturated 4- to8-membered ring optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of oxygen, sulfur and nitrogen, abicyclic ring system consisting of a partially saturated, fullyunsaturated or fully saturated 5- or 6-membered ring, optionally having1 to 4 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen, fused to a partially saturated, fullysaturated or fully unsaturated 5- or 6-membered ring, optionally having1 to 4 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen;

A¹ for each occurrence is independently optionally substituted, in oneor optionally both rings if A¹ is a bicyclic ring system, with up tothree substituents, each substituent independently selected from thegroup consisting of F, Cl, Br, I OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶,—C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo, (C₁-C₆)alkyl, nitro, cyano, benzyl,—S(O)_(m)(C₁-C₆)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy,phenylalkyloxy, halophenyl, methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶),—SO₂N(X⁶)(X⁶), —N(X⁶)SO₂-phenyl, —N(X⁶)SO₂X⁶, —CONX¹¹X¹², —SO₂NX¹¹X¹²,—NX⁶SO₂X¹², —NX⁶CONX¹¹X¹², —NX⁶SO₂NX¹¹X¹², —NX⁶C(O)X¹², imidazolyl,thiazolyl or tetrazolyl, provided that if A¹ is optionally substitutedwith methylenedioxy then it can only be substituted with onemethylenedioxy;

where X¹¹ is hydrogen or optionally substituted (C₁-C₆)alkyl; theoptionally substituted (C₁-C₆)alkyl defined for X¹¹ is optionallyindependently substituted with phenyl, phenoxy, (C₁-C₆)alkoxycarbonyl,—S(O)_(m)(C₁-C₆)alkyl 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3(C₁-C₁₀)alkanoyloxy or 1 to 3 (C₁-C₆)alkoxy;

X¹² is hydrogen, (C₁-C₆)alkyl, phenyl, thiazolyl, imidazolyl, furyl orthienyl, provided that when X¹² is not hydrogen, X¹² is optionallysubstituted with one to three substituents independently selected fromthe group consisting of Cl, F, CH₃, OCH₃, OCF₃ and CF₃; or X¹¹ and X¹²are taken together to form —(CH₂)_(r)—L¹—(CH₂)_(r)—; L¹ is C(X²)(X²), O,S(O)_(m) or N(X²);

r for each occurrence is independently 1, 2 or 3;

X² for each occurrence is independently hydrogen, optionally substituted(C₁-C₆)alkyl, or optionally substituted (C₃-C₇)cycloalkyl, where theoptionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl in the definition of X² are optionally independentlysubstituted with —S(O)_(m)(C₁-C₈)alkyl, —C(O)OX³, 1 to 5 halogens or 1to 3 OX³;

X³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl;

X⁶ is independently hydrogen, optionally substituted (C₁-C₆)alkyl,(C₂-C₆)halogenated alkyl, optionally substituted (C₃-C₇)cycloalkyl,(C₃-C₇)-halogenatedcycloalkyl, where optionally substituted (C₁-C₆)alkyland optionally substituted (C₃-C₇)cycloalkyl in the definition of X⁶ isoptionally independently substituted by 1 or 2 (C₁-C₄)alkyl, hydroxyl,(C₁-C₄)alkoxy, carboxyl, CONH₂, —S(O)_(m)(C₁-C₆)alkyl, carboxylate(C₁-C₄)alkyl ester, or 1H-tetrazol-5-yl; or

when there are two X⁶ groups on one atom and both X⁶ are independently(C₁-C₆)alkyl, the two (C₁-C₆)alkyl groups may be optionally joined and,together with the atom to which the two X⁶ groups are attached, form a4- to 9-membered ring optionally having oxygen, sulfur or NX⁷;

X⁷ is hydrogen or (C₁-C₆)alkyl optionally substituted with hydroxyl; and

m for each occurrence is independently 0, 1 or 2;

with the proviso that:

X⁶ and X¹² cannot be hydrogen when it is attached to C(O) or SO₂ in theform C(O)X⁶, C(O)X¹², SO₂X⁸ or SO₂X¹²; and

when R⁶ is a bond then L is N(X²) and each r in the definition—(CH₂)_(r)—L—(CH₂)_(r)— is independently 2 or 3.

A preferred group of compounds, designated the “A Group”, contains thosecompounds having the formula I as shown hereinabove wherein X⁴ ishydrogen; R⁴ is hydrogen or methyl; R⁷ is hydrogen or (C₁-C₃)alkyl; R⁸is hydrogen or (C₁-C₃)alkyl optionally substituted with one or twohydroxyl groups;

R⁶ is

where Z¹ is a bond and a is 0 or 1;

X⁵ and X^(5a) are each independently hydrogen, trifluoromethyl, phenyl,optionally substituted (C₁-C₆)alkyl;

where the optionally substituted (C₁-C₆)alkyl is optionally substitutedwith OX², imidazolyl, phenyl, indolyl, p-hydroxyphenyl,(C₅-C₇)cycloalkyl, —S(O)_(m)(C₁-C₆)alkyl, —N(X²)(X²) or —C(O)N(X²)(X²);

or X⁵ and R⁷ are taken together to form a (C₁-C₅)alkylene bridge, andthe other substituents not defined for the “A Group” compounds are asdefined for formula (I) hereinabove.

A group of compounds, which is preferred among the “A Group” ofcompounds, designated the “B Group”, contains those compounds of the “AGroup”, having the formula I as shown hereinabove, wherein b is 0; X⁵and X^(5a) are each independently hydrogen, (C₁-C₃)alkyl orhydroxy(C₁-C₃)alkyl; R³ is selected from the group consisting of1-indolyl-CH₂—, 2-indolyl-CH₂—, 3-indolyl-CH₂—, 1-naphthyl-CH₂—,2-naphthyl-CH₂—, 1-benzimidazolyl-CH₂—, 2-benzimidazolyl-CH₂—,phenyl-(C₁-C₄)alkyl- , 2-pyridyl-(C₁-C₄)alkyl—, 3-pyridyl-(C₁-C₄)alkyl-,4-pyridyl-(C₁-C₄)alkyl-, phenyl-CH₂—S—CH₂—, thienyl-(C₁-C₄)alkyl-,phenyl-(C₀-C₃)alkyl-O—CH₂—, phenyl-CH₂—O-phenyl-CH₂—, and3-benzothienyl-CH₂—;

where the aryl portion(s) of the groups defined for R³ are optionallysubstituted with one to three substituents, each substituent beingindependently selected from the group consisting of methylenedioxy, F,Cl, CH₃, OCH₃, OCF₃, OCF₂H and CF₃.

A group of compounds, which is preferred among the “B Group” ofcompounds, designated the “C Group”, contain those compounds of the “BGroup”, having the formula I as shown hereinabove, wherein R⁴ ishydrogen; a is 0; n is 1 or 2; w is 0 or 1; X⁵ and X^(5a) are eachindependently, hydrogen, methyl or hydroxymethyl, provided that when X⁵is hydrogen then X^(5a) is not hydrogen;

R⁷ and R⁸ are each hydrogen; and

R³ is phenyl-CH₂—O—CH₂—, phenyl-CH₂—S—CH₂—, 1-naphthyl-CH₂—,2-naphthyl-CH₂—, phenyl-(CH₂)₃— or 3-indolyl-CH₂—;

where the aryl portion of the groups defined for R³ is optionallysubstituted with one to three substituents, each substituent beingindependently selected from the group consisting of fluoro, chloro,methyl, OCH₃, OCF₂H, OCF₃ and CF₃.

A group of compounds, which is preferred among the “C Group” ofcompounds, designated the “D Group”, contains those compounds of the “CGroup”, having the formula I as shown hereinabove, wherein R¹ is—(CH₂)_(t)—A¹, —(CH₂)_(q)—(C₃-C₇)cycloalkyl or (C₁-C₁₀)alkyl;

where A¹ in the definition of R¹ is optionally substituted with one tothree substituents, each substituent being independently selected fromthe group consisting of fluoro, chloro, methyl, OCH₃, OCF₂H, OCF₃ andCF₃;

the cycloalkyl and alkyl groups in the definition of R¹ are optionallysubstituted with (C₁-C₄)alkyl, hydroxyl, (C₁—C₄)alkoxy, carboxyl, CONH₂,—S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester, 1H-tetrazol-5-yl or 1 to3 fluoro;

Y is O; R² is hydrogen, —(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl, phenyl or(C₁-C₈)alkyl where the (C₁-C₈)alkyl group is optionally substituted withhydroxyl, —CF₃ or 1 to 3 halogen.

A group of compounds, which is preferred among the “D Group” ofcompounds, designated the “E Group”, contain those compounds of the “DGroup” wherein w is 0 and n is 1.

Another group of compounds, which is preferred among the “D Group” ofcompounds, designated the “F Group”, are those compounds of the “DGroup”, having the formula I as shown hereinabove, wherein e is 0; n andw are each 1;

R¹ is —(CH₂)_(t)—A¹;

where A¹ in the definition of R¹ is phenyl, thienyl, thiazolyl, pyridylor pyrimidyl which is optionally substituted with one to threesubstituents, each substituent being independently selected from thegroup consisting of F, Cl, Me, OMe, CF₃, OCF₃ and OCF₂H;

t is 0, 1 or 2;

and R³ is phenyl-CH₂—O—CH₂—, phenyl-(CH₂)₃— or 3-indolyl-CH₂—, where thearyl portion is optionally substituted with one to three substituents,each substituent being independently selected from the group consistingof F, Cl, Me, OMe, CF₃, OCF₃ or OCF₂H.

A group of compounds, which is preferred among the “F Group” ofcompounds, designated the “G Group”, contains those compounds of the “FGroup”, having the formula I as shown hereinabove, wherein X⁵ and X^(5a)are each methyl; R¹ is —CH₂-phenyl, —CH₂-4-fluoro-phenyl, —CH₂-pyridylor —CH₂-thiazolyl and R² is hydrogen, methyl, ethyl, t-butyl or —CH₂CF₃.

A group of compounds, which is preferred among the “G Group” ofcompounds, designated the “G¹ Group”, contains those compounds of the “GGroup”, and have the formula

the racemic-diastereomeric mixtures and optical isomers of saidcompounds wherein

R¹ is —CH₂-phenyl, R² is methyl and R³ is —(CH₂)₃-phenyl;

R¹ is —CH₂-phenyl, R² is methyl and R³ is 3-indolyl-CH₂—;

R¹ is —CH₂-phenyl, R² is ethyl and R³ is 3-indolyl-CH₂—;

R¹ is —CH₂-4-fluoro-phenyl, R² is methyl and R³ is 3-indolyl-CH₂—;

R¹ is —CH₂-phenyl, R² is methyl and R³ is —CH₂—O—CH₂-phenyl;

R¹ is —CH₂-phenyl, R² is ethyl and R³ is —CH₂—O—CH₂-phenyl;

R¹ is —CH₂-phenyl, R² is —CH₂—CF₃ and R³ is —CH₂—O—CH₂-phenyl;

R¹ is —CH₂-4-fluoro-phenyl, R² is methyl and R³ is —CH₂—O—CH₂-phenyl;

R¹ is —CH₂-phenyl, R² is t-butyl and R³ is —CH₂—O—CH₂-phenyl; or

R¹ is —CH₂-phenyl, R² is methyl and R³ is—CH₂—O—CH₂-3,4-di-fluoro-phenyl.

The diastereomeric mixture of2-amino-N-[2-(3a-(R,S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-(3,4-difluoro-benzyl-oxymethyl)-2-oxo-ethyl]-2-methyl-propionamideis preferred amount the “G¹ Group” of compounds and the separated 3a-(R)and 3a-(S) isomers are preferred of the diastereomeric mixture.

A group of compounds, which is preferred among the “G Group” ofcompounds, designated the “H Group”, contains those compounds of the “GGroup”, having the formula I as shown hereinabove, wherein R¹ is—CH₂-phenyl and R³ is phenyl-(CH₂)₃—.

The diastereomeric mixture of2-amino-N-[1-(3a-(R,S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-4-phenyl-(R)-butyl]-isobutyramideis preferred among the “H Group” of compounds and the separated 3a-(R)and 3a-(S) isomers are preferred of the diastereomeric mixture.

A group of compounds, which is preferred among the “G Group” ofcompounds, designated the “I Group”, contains those compounds of the “GGroup” wherein R¹ —CH₂-phenyl or —CH₂-4-fluoro-phenyl and R³ is3-indolyl-CH₂—.

The diastereomeric mixture of2-amino-N-[2-(3a-(R,S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridine-5-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramideis also preferred among the “I Group” of compounds and the separated3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture.

The diastereomeric mixture of2-amino-N-[2-(3a-(R,S)-benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridine-5-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramideis also preferred among the “I Group” of compounds and the separated3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture.

The diastereomeric mixture of2-amino-N-[2-(3a-(R,S)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridine-5-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramideis also preferred among the “I Group” of compounds and the separated3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture.

A group of compounds which is preferred among the “G Group” ofcompounds, designated the “J Group”, contains those compounds of the “GGroup” wherein R¹ is —CH₂-phenyl or —CH₂-4-fluoro-phenyl and R³ isphenyl-CH₂—O—CH₂—.

The diastereomeric mixture of2-amino-N-[2-(3a-(R,S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridine-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideis preferred among the “J Group” of compounds, the separated 3a-(R) and3a-(S) isomers are preferred of the diastereomeric mixture, the 3a-(R)isomer is preferred over the 3a-(S) isomer, and the L-tartaric acid saltof the 3a-(R) isomer is a preferred salt.

The diastereomeric mixture of2-amino-N-[2-(3a-(R,S)-benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridine-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideis also preferred among the “J Group” of compounds and the separated3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture.

The diastereomeric mixture of2-amino-N-[2-(3a-(R,S)-benzyl-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideis also preferred among the “J Group” of compounds, the separated 3a-(R)and 3a-(S) isomers are preferred of the diasteromeric mixture and the3a-(R) isomer is preferred over the 3a-(S) isomer.

The diastereomeric mixture of2-amino—N—{(1-(R)-benzyloxymethyl-2-[3-a-(R,S)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-oxo-ethyl}-isobutyramideis also preferred among the “J Group” of compounds and the separated3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture.

The diastereomeric mixture of2-amino—N—[2-(3a-(R,S)-benzyl-2-tert-butyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideis also preferred among the “J Group” of compounds and the separated3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture.

A group of compounds which is preferred among the “D Group” ofcompounds, designated the “K Group”, contains those compounds of the “DGroup” wherein e is 1; n is 1; w is 1; R¹ is —(CH₂)_(t)-A¹;

where A¹ in the definition of R¹ is phenyl, thienyl, thiazolyl, pyridylor pyrimidyl which is optionally substituted with one to threesubstituents, each substituent being independently selected from thegroup consisting of F, Cl, Me, OMe, CF₃, OCF₃ and OCF₂H;

t is 0, 1 or 2;

and R³ is phenyl-CH₂—O—CH₂—, phenyl-CH₂)₃— or 3-indolyl-CH₂—, where thearyl portion is optionally substituted with one to three substituents,each substituent being independently selected from the group consistingof F, Cl, Me, OMe, CF₃, OCF₃ or OCF₂H.

A group of compounds which is preferred among the “K Group” ofcompounds, designated the “L Group”, are those compounds of the “KGroup” wherein X⁵ and X^(6a) are each methyl; R¹ is -CH₂-phenyl,-CH₂-4-fluoro-phenyl, —CH₂-pyridyl or —CH₂-thiazolyl and R² is hydrogen,methyl, ethyl, t-butyl or —CH₂CF₃.

A group of compounds which is preferred among the “L Group”, designatedthe “L¹ Group”, are those compounds of the “L Group” wherein R¹ is—CH₂-phenyl; R² is hydrogen or methyl and R³ is —CH₂—O—CH₂-phenyl.

The diastereomeric mixture of2-amino—N—[2-(3a-(R,S)-benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideis preferred among the “J Group”, the separated 3a-(R) and 3a-(S)isomers are preferred of the diastereomeric mixture and the 3a-(R)isomer is preferred over the 3a-(S) isomer.

Another group of compounds, which is preferred among the “a Group” ofcompounds, designated the “M Group”, contains those compounds of the “AGroup”, having the formula I as shown hereinabove, wherein b is 0; X⁵and X^(5a) are each independently hydrogen, (C₁-C₃)alkyl orhydroxy(C₁-C₃)alkyl;

R³ is selected from the group consisting of 1-indolyl-CH₂—,2-indolyl-CH₂—, 3-indolyl-CH₂—, 1-naphthyl-CH₂—, 2-naphthyl-CH₂—,1-benzimidazolyl-CH₂—, 2-benzimidazolyl-CH₂—, phenyl-(C₁-C₄)alkyl—,2-pyridyl-(C₁-C₄)alkyl—, 3-pyridyl-(C₁-C₄alkyl—,4-pyridyl-(C₁-C₄)alkyl—, phenyl-CH₂—S—CH₂—, thienyl-(C₁-C₄)alkyl—,phenyl-(C₀-C₃)alkyl—O—CH₂—, phenyl-CH₂—O—phenyl-CH₂—,3-benzothienyl-CH₂—, thienyl-CH₂—O—CH₂—, thiazolyl-CH₂—O—CH₂—,pyridyl-CH₂—O—CH₂—, pyrimidyl-CH₂—O—CH₂— and phenyl- andphenyl—O—CH₂-CH₂;

where the aryl portion(s) of the groups defined for R³ are optionallysubstituted with one to three substituents, each substituent beingindependently selected from the group consisting of methylenedioxy, F,Cl, CH₃, OCH₃, OCF₃, OCF₃H and CF₃.

A group of compounds, which is preferred among the “M Group” ofcompounds, designated the “M¹ Group”, contains those compounds of the “MGroup”, having the formula I as shown hereinabove, wherein R⁴ ishydrogen; a is 0; n is 1; w is 1; e is 0; X⁵ and X^(5a) are eachindependently, hydrogen, methyl or hydroxymethyl, provided that when X⁵is hydrogen then X^(5a) is not hydrogen; R⁷ and R⁸ are each hydrogen; Yis oxygen; R² is hydrogen, methyl, ethyl, propyl, i-propyl, t-butyl,—CH₂CF₃, CF₃ or —CH₂-cyclopropyl; R¹ is CH_(z)-A¹; where A¹ in thedefinition of R¹ is phenyl, thienyl, thiazolyl, pyridyl or pyrimidylwhich is optionally substituted with one to three substituents, eachsubstituent being independently selected from the group consisting of F,Cl, Me, OMe, CF₃, OCF₃ and OCF₂H; and R³ is phenyl-CH₂—O—CH₂—,phenyl-(CH₂)₃—, 3-indolyl-CH₂—, thienyl-CH₂O-CH₂—, thiazolyl-CH₂—O—CH₂—,pyridyl-CH₂—O—CH₂—, pyrimidyl-CH₂—O—CH₂— or phenyl—O—CH₂-CH₂, where thearyl portion is optionally substituted with one to three substituents,each substituent being independently selected from the group consistingof F, Cl, Me, OMe, CF₃, OCF₃ and OCF₂H.

A group of compounds, which is preferred among the “M¹ Group” ofcompounds, designated the “N Group”, contains those compounds of the “M¹Group”, having the formula I as shown hereinabove, wherein X⁵ and X^(5a)are each methyl; R² is methyl, ethyl, or —CH₂CF₃; A¹ is phenyloptionally substituted with one to three substituents, each substituentbeing independently selected from the group consisting of F, Cl, Me,OMe, CF₃, OCF₃ and OCF₂H; R³ is phenyl-CH₂—O—CH₂—, phenyl-(CH₂)₃— orthienyl-CH₂—O—CH₂— where the aryl portion is optionally substituted withone to three substituents, each substituent being independently selectedfrom the group consisting of F, Cl, Me, OMe, CF₃, OCF₃ and OCF₂H.

Another group of compounds, which is preferred among the “M¹ Group” ofcompounds, designated the “O Group”, contains those compounds of the “M¹Group”, having the formula I as shown hereinabove, wherein X⁵ and X^(5a)are each methyl; R² is methyl, ethyl, or CH₂CF₃; A¹ is 2-pyridyl or3-pyridyl optionally substituted with one to two substituents, eachsubstituent being independently selected from the group consisting of F,Cl, Me, OMe, CF₃, OCF₃ and OCF₂H; R³ is phenyl-CH₂—O—CH₂—,phenyl-(CH₂)₃— or thienyl-CH₂—O—CH₂— where the aryl portion isoptionally substituted with one to three substituents, each substituentbeing independently selected from the group consisting of F, Cl, Me,OMe, CF₃, OCF₃ and OCF₂H.

Another group of compounds, which is preferred among the “M¹ Group” ofcompounds, designated the “P Group”, contains those compounds of the “M¹Group”, having the formula I as shown hereinabove, wherein X⁵ and X^(5a)are each methyl; R² is methyl, ethyl, or CH₂CF₃; A¹ is phenyl optionallysubstituted with one to three substituents, each substituent beingindependently selected from the group consisting of F, Cl, Me, OMe, CF₃,OCF₃ and OCF₂H; R³ is 2-pyridyl-CH₂—O—CH₂—, or 3-pyridyl-CH₂—O—CH₂—where the aryl portion is optionally substituted with one to twosubstituents, each substituent being independently selected from thegroup consisting of F, Cl, Me, OMe, CF₃, OCF₃ and OCF₂H.

A group of compounds, which is preferred among the “O Group” ofcompounds, designated the “Q Group”, contains those compounds of the “OGroup”, having the formula

the racemic-diastereomeric mixtures and optical isomers of saidcompounds wherein

R² is methyl; A¹ is 2-pyridyl; and R³ is —CH₂—O—CH₂-phenyl;

R² is CH₂CF₃; A¹ is 2-pyridyl; and R³ is —CH₂—O—CH₂-3-chloro-phenyl;

R² is CH₂CF₃; A¹ is 2-pyridyl; and R³ is —CH₂—O—CH₂-4-chloro-phenyl;

R² is CH₂CF₃; A¹ is 2-pyridyl; and R³ is—CH₂—O—CH₂-2,4-di-chloro-phenyl;

R² is CH₂CF₃; A¹ is 2-pyridyl; and R³ is —CH₂—O—CH₂-3-chloro-thiophene;or

R² is CH₂CF₃; A¹ is 2-pyridyl; and R³ is—CH₂—O—CH₂-2,4-di-fluoro-phenyl.

The diastereomeric mixture of2-amino—N—[1-(R)-benzyloxymethyl-2-(2-methyl-3-oxo-3a-(R,S)-pyridin-2-ylmethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-2-methyl-propionamideis preferred among the “Q Group” of compounds and the separated 3a-(R)and 3a-(S) isomers are preferred of the diastereomeric mixture.

The diastereomeric mixture of2-amino—N—{1-(R)-(3-chloro-benzyloxy-methyl)-2-oxo-2-[3-oxo-3a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide is preferred among the“Q Group” of compounds and the separated 3a-(R) and 3a-(S) isomers arepreferred of the diastereomeric mixture.

The diastereomeric mixture of2-amino—N—{1-(R)-(4-chloro-benzyloxy-methyl)-2-oxo-2-[3-oxo-3a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide is preferred among the“Q Group” of compounds and the separated 3a-(R) and 3a-(S) isomers arepreferred of the diastereomeric mixture.

The diastereomeric mixture of2-amino—N—{1-(R)-(2,4-dichloro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide is preferred among the“Q Group” of compounds and the separated 3-a-(R) and 3a-(S) isomers arepreferred of the diastereomeric mixture.

The diastereomeric mixture of2-amino—N—{1-(R)-(4-chloro-thiophen-2-ylmethoxymethyl)-2-oxo-2-[3-oxo-3a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,5,7-hexahydro-pyrazolo[3,4-c]pyridin-6-yl]-ethyl}-2-methyl-propionamide is preferred among the“Q Group” of compounds of the separated 3a-(R) and 3a-(S) isomers arepreferred of the diastereomeric mixture.

The diastereomeric mixture of2-amino—N—{1-(R)-(2,4-difluoro-benzyloxy-methyl)-2-oxo-2-[3-oxo-3a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamideis preferred among the “Q Group” of compounds and the separated 3a-(R)and 3a-(S) isomers are preferred of the diastereomeric mixture.

A group of compounds which contains intermediates useful in synthesizingthe compounds of formula (I) are of the formula

the racemic-diastereomeric mixtures and optical isomers of saidcompounds and the pharmaceutically-acceptable salts thereof, wherein eor 0 or 1; n and w are each independently 0, 1 or 2, provided that w andn cannot both be 0 at the same time;

R¹ is hydrogen, —CN, —(CH₂)_(q)N(X⁵)C(O)X⁶,—(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)-A¹, —(CH₂)_(q)N(X⁶)SO₂(CH₂)_(t)-A¹,—(CH₂)_(q)N(X⁶)SO₂X⁶, —(CH₂)_(q)N(X⁵)C(O)N(X⁵)(CH₂)_(t)-A¹,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)-A¹, —(CH₂)_(q)C(O)OX⁶,—(CH₂)_(q)C(O)O(CH₂)_(t)-A¹, —(CH₂)_(q)OX⁶, —(CH₂)_(q)OC(O)X⁶,—(CH₂)_(q)OC(O)(CH₂)_(t)-A¹, —(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)-A¹,—(CH₂)_(q)OC(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)-A¹,—(CH₂)_(q)N(X⁶)C(O)OX⁶, —(CH₂)_(q)N(X⁶)SO₂N(X⁶)(X⁶),—(CH₂)_(q)S(O)_(m)X⁶, —(CH₂)_(q)S(O)_(m)(CH₂)_(t)-A¹, —(C₁-C₁₀)alkyl,—(CH₂)_(t)-A¹, —(CH₂)_(q)-(C₃-C₇)cycloalkyl, —(CH₂)_(q)-Y¹-(C₁-C₆)alkyl,—(CH₂)_(q)-Y¹-(CH₂)_(t)-A¹ or —(CH₂)_(q)-Y¹-(CH₂)₁-(C₃-C₇)cycloalkyl;

where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxyl, (C₁-C₄)alkoxy,carboxyl, CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl,1H-tetrazol-5-yl or 1 to 3 fluoro; Y¹ is O, S(O)_(m), —C(O)NX⁶, —CH═CH—,—C≡C—, —N(X⁶)C(O)—, —C(O)NX⁶—, —C(O)O—, —OC(O)N(X⁶)— or —OC(O)—; q is 0,1, 2, 3 or 4; t is 0, 1, 2 or 3;

said (CH₂)_(q) group and (CH₂)_(t) group may each be optionallysubstituted with 1 to 3 fluoro, 1 or 2 (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy, carbonyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,or 1H-tetrazol-5-yl;

R² is hydrogen, (C₁-C₈)alkyl, —(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl,—(C₁-C₄)alkyl-A¹ or A¹;

where the alkyl groups and the cycloalkyl groups in the definition of R²are optionally substituted by hydroxy, —C(O)OX⁶, —C(O)N(X⁶)(X⁶),—N(X⁶)(X⁶), —S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹, —C(O)(X⁶), CF₃, CN or 1 to 3halogen;

A¹ for each occurrence is independently (C₅-C₇)cycloalkenyl, phenyl or apartially saturated, fully saturated or fully unsaturated 4- to8-membered ring optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of oxygen, sulfur and nitrogen, or abicyclic ring system consisting of a partially saturated, fullyunsaturated or fully saturated 5- or 6-membered ring, optionally having1 to 4 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen, fused to a partially saturated, fullysaturated or fully unsaturated 5- or 6-membered ring, optionally having1 to 4 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen;

A¹ for each occurrence is independently optionally substituted, in oneor optionally both rings if A¹ is a bicyclic ring system, with up tothree substituents, each substituent independently selected from thegroup consisting of F, Cl, Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶,—C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo, (C₁-C₆alkyl, nitro, cyano, benzyl,—S(O)_(m)(C₁-C₆)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy,phenylalkyloxy, halophenyl, methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶),—SO₂N(X⁶)(X⁶), —N(X⁶)SO₂-phenyl, —N(X⁶)SO₂X⁶, —CONX¹¹X¹², —SO₂NX¹¹X¹²,—NX⁶SO₂X¹², —NX⁶CONX¹¹X¹², —NX⁶SO₂NX¹¹X¹², —NX⁶C(O)X¹², imidazolyl,thiazolyl and tetrazolyl, provided that if A¹ is optionally substitutedwith methylenedioxy then it can only be substituted by onemethylenedioxy;

where X¹¹ is hydrogen or optionally substituted (C₁-C₆)alkyl; theoptionally substituted (C₁-C₆)alkyl defined for X¹¹ is optionallyindependently substituted with phenyl, phenoxy, (C₁-C₆)alkoxycarbonyl,—S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3(C₁-C₁₀)alkanoyloxy or 1 to 3 (C₁-C₆)alkoxy;

X¹² is hydrogen, (C₁-C₆)alkyl, phenyl, thiazolyl, imidazolyl, furyl orthienyl, provided that when X¹² is not hydrogen, X¹² is optionallysubstituted with one to three substituents independently selected fromthe group consisting of Cl, F, CH₃, OCH₃, OCF₃ and CF₃;

or X¹¹ and X¹² are taken together to form —(CH₂)₁-L¹-(CH₂)₁—;

L¹ is C(X²)(X²), O, S(O)_(m) or N(X²);

r for each occurrence is independently 1, 2 or 3;

X² for each occurrence is independently hydrogen, optionally substituted(C₁-C₆) alkyl, or optionally substituted (C₃-C₇)cycloalkyl, where theoptionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl in the definition of X² are optionally independentlysubstituted with —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halogens or 1to 3 OX³;

X³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl;

X⁶ for each occurrence is independently hydrogen, optionally substituted(C₁-C₆) alkyl, (C₂-C₆)halogenated alkyl, optionally substituted (C₃-C₇)cycloalkyl, (C₃-C₇)-halogenated cycloalkyl, where optionally substituted(C₁-C₆)alkyl and optionally substituted (C₃-C₇)cycloalkyl in thedefinition of X⁶ is optionally independently substituted by, hydroxy,(C₁-C₄)alkoxy, carbonyl, CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl,1H-tetrazol-5-yl or 1 or 2 (C₁-C₄)alkyl; or

where there are two X⁶ groups on one atom and both X⁶ are (C₁-C₆)alkyl,the two (C₁-C₆)alkyl groups may be optionally joined and, together withthe atom to which the two X⁶ groups are attached, form a 4- to9-membered ring optionally having oxygen, sulfur or NX⁷;

X⁷ is hydrogen or (C₁-C₆)alkyl optionally substituted with hydroxyl; andm for each occurrence is independently 0, 1 or 2;

with the proviso that:

X⁶ and X¹² cannot be hydrogen when it is attached to C(O) or SO₂ in theform C(O)X⁶, C(O)X¹², SO₂X⁶ or SO₂X¹²; and

when R² is hydrogen then R¹ is not —CH═CH-phenyl.

A group of intermediate compounds preferred among the foregoing group offormula (II), designated “Group AA”, contains those compounds wherein wis 0 or 1; n is 1; R¹ is hydrogen, —(CH₂)_(q)-(C₃-C₇)cycloalkyl,—(CH₂)_(t)-A¹ or (C₁-C₁₀)alkyl where the (C₁-C₁₀)alkyl and(C₃-C₇)cycloalkyl groups are optionally substituted with 1 to 3 fluoroand A¹ in the definition of R¹ is optionally substituted with 1 to 3substituents independently selected from the group consisting of F, Cl,Me, methoxy, CF₃, OCF₃ and OCF₂H; R² is hydrogen, (C₁-C₈)alkyl,(C₀-C₃)alkyl-(C₃-C₇)cycloalkyl, phenyl, or (C₁-C₃)alkyl-phenyl where thealkyl and phenyl groups are optionally substituted with 1 to 3substituents independently selected from the group consisting of F, CF₃,OH and methoxy.

A group of compounds preferred among the “AA Group” compounds,designated “BB Group”, contains those compounds of “AA Group” wherein wis 1; e is 0; R¹ is —CH₂-pyridyl, —CH₂-thiazolyl, or —CH₂-phenyloptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of fluoro and chloro; and R² is hydrogen,(C₁-C₄)alkyl or phenyl where the (C₁-C₄)alkyl or phenyl groups in thedefinition of R² is optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of fluoro, hydroxy ormethoxy.

Compounds which are preferred among the “BB Group” compounds is thediastereomeric mixture of a compound wherein R¹ is —CH₂-phenyl and R² ismethyl or hydrogen; and the separated 3-a-(R) and 3a-(S) isomers arepreferred of the diastereomeric mixture.

Another group of intermediate compounds which are useful in thesynthesis of the compounds of formula (I) have the formula

the racemic-diastereomeric mixtures and optical isomers of saidcompounds wherein Z¹⁰⁰ is methyl, BOC, CBZ, CF₃C(O)—, FMOC, TROC,trityl, tosyl, CH₃C(O)— or optionally substituted benzyl whichoptionally substituted with methoxy, dimethoxy or nitro; e is 0 or 1; nand w are each independently 0, 1 or 2, provided that w and n cannotboth be 0 at the same time;

R¹ is hydrogen, —CN, —(CH₂)_(q)N(X⁶)C(O)X⁶,—(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)-A¹, —(CH₂)_(q)N(X⁶)SO₂(CH₂)_(t)-A¹,—(CH₂)_(q)N(X⁶)SO₂X⁶, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)-A¹,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)-A¹, —(CH₂)_(q)C(O)OX⁶,—(CH₂)_(q)C(O)O(CH₂)_(t)-A¹, —(CH₂)_(q)OX⁶, —(CH₂)_(q)OC(O)X⁶,—(CH₂)_(q)OC(O)(CH₂)_(t)-A¹, —(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)-A¹,—(CH₂)_(q)OC(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)-A¹,—(CH₂)_(q)N(X⁶)C(O)OX⁶, —(CH₂)_(q)N(X⁶)SO₂N(X⁶)(X⁶),—(CH₂)_(q)S(O)_(m)X⁶, —(CH₂)_(q)S(O)_(m)(CH₂)_(t)-A¹, —(C₁-C₁₀)alkyl,—(CH₂)_(t)-A¹, —(CH₂)_(q)-(C₃-C₇)cycloalkyl, —(CH₂)_(q)-Y¹-(C₁-C₆)alkyl,—(CH₂)_(q)-Y¹-(CH₂)_(t)-A¹ or —(CH₂)_(q)-Y¹-(CH₂)_(t)-(C₃-C₇)cycloalkyl;

where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hyroxy, (C₁-C₄)alkoxy,carboxyl, COHN₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl,1H-tetrazol-5-yl or 1 to 3 fluoro Y¹ is O, S(O)_(m), —C(O)NX⁶, —CH═CH—,—C≡C—, —N(X⁶)C(O), —C(O)NX⁶, —C(O)O, —OC(O)N(X⁶) or —OC(O);

q is 0, 1, 2, 3 or 4;

t is 0, 1, 2 or 3;

said (CH₂)_(q) group and (CH₂)_(t) group may each be optionallysubstituted with hydroxy, (C₁-C₄)alkoxy, carboxyl, —COHN₂,—S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl, 1H-tetrazol-5-yl, 1 to 3 fluoroor 1 or 2 (C₁-C₄)alkyl;

R² is hydrogen, (C₁-C₈)alkyl, —(C₀-C₃)alkyl-(C₃-C₆)cycloalkyl,—(C₁-C₄)alkyl-A¹ or A¹;

where the alkyl groups and the cycloalkyl groups in the definition of R²are optionally substituted with hydroxyl, —C(O)OX⁶, —C(O)N(X⁶)(X⁶),—N(X⁶)(X⁶), —S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹, —C(O)(X⁶), CF₃, CN or 1 to 3halogen;

A¹ for each occurrence is independently (C₅-C₇)cycloalkenyl, phenyl or apartially saturated, fully saturated or fully unsaturated 4- to8-membered ring optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of oxygen, sulfur and nitrogen, or abicyclic ring system consisting of a partially saturated, fullyunsaturated or fully saturated 5- or 6-membered ring, optionally having1 to 4 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen, fused to a partially saturated, fullysaturated or fully unsaturated 5- or 6-membered ring, optionally having1 to 4 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen;

A¹ for each occurrence is independently optionally substituted, in oneor optionally both rings if A¹ is a bicyclic ring system, with up tothree substituents, each substituent independently selected from thegroup consisting of F, Cl, Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶,—C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo, (C₁-C₆)alkyl, nitro, cyano, benzyl,—S(O)_(m)(C₁-C₆)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy,phenylalkyloxy, halophenyl, methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁵),—SO₂N(X⁶)(X⁶), —N(X⁶)SO₂-phenyl, —N(X⁶)SO₂X⁶, —CONX¹¹X¹², —SO₂NX¹¹X¹²,—NX⁶SO₂X¹², —NX⁶CONX¹¹X¹², —NX⁶SO₂NX¹¹X¹², —NX⁶C(O)X¹², imidazolyl,thiazolyl and tetrazolyl, provided that if A¹ is optionally substitutedwith methylenedioxy then it can only be substituted with onemethylenedioxy;

where X¹¹ is hydrogen or optionally substituted (C₁-C₆)alkyl; theoptionally substituted (C₁-C₈)alkyl defined for X¹¹ is optionallyindependently substituted with phenyl, phenoxy, (C₁-C₆) alkoxycarbonyl,—S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3(C₁-C₁₀)alkanoyloxy or 1 to 3 (C₁-C₆)alkoxy;

X¹² is hydrogen, (C₁-C₆)alkyl, phenyl, thiazolyl, imidazolyl, buryl orthienyl, provided that when X¹² is not hydrogen, X¹² is optionallysubstituted with one to three substituents independently selected fromthe group consisting of Cl, F, CH₃, OCH₃, OCF₃ and CF₃; or X¹¹ and X¹²are taken together to form —(CH₂)_(r)-L¹-(CH₂)_(r)—;

L^(f) is C(X²)(X²), O, S(O)_(m) or N(X²);

r for each occurrence is independently 1, 2 or 3;

X² for each occurrence is independently hydrogen, optionally substituted(C₁-C₆) alkyl, or optionally substituted (C₃-C₇)cycloalkyl, where theoptionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl, where the optionally substituted (C₁-C₆)alkyl andoptionally substituted (C₃-C₇)cycloalkyl in the definition of X² areoptionally independently substituted with —S(O)_(m)(C₁-C₆)alkyl,—C(O)OX³, 1 to 5 halogens or 1 to 3 OX³;

X³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl;

X⁶ for each occurrence is independently hydrogen, optionally substituted(C₁-C₆)alkyl, (C₂-C₆)halogenated alkyl, optionally substituted(C₃-C₇)cycloalkyl, (C₃-C₇)-halogenatedcycloalkyl, where optionallysubstituted (C₁-C₆)alkyl and optionally substituted (C₃-C₇)cycloalkyl inthe definition of X⁶ is optionally independently substituted withhydroxy, (C₁-C₄)alkoxy, carbonyl, COHN₂, —S(O)_(m)(C₁-C₆)alkyl,—CO₂(C₁-C₄)alkyl, 1H-tetrazol-5-yl or 1 or 2 (C₁-C₄)alkyl; or

where there are two X⁶ groups on one atom and both X⁶ are (C₁-C₆)alkyl,the two (C₁-C₆)alkyl groups may be optionally joined and, together withthe atom to which the two X⁶ groups are attached, form a 4- to 9-membered ring optionally having oxygen, sulfur or NX⁷;

X⁷ is hydrogen or (C₁-C₆)alkyl optionally substituted with hydroxyl; andm for each occurence is independently 0, 1 or 2;

with the proviso that:

X⁶ and X¹² cannot be hydrogen when it is attached to C(O) or SO₂ in theform C(O)X⁶, C(O)X¹², SO₂X⁶ or SO₂X¹²;

when R² is hydrogen then R¹ is not —CH═CH—penyl;

when R² is H and R¹ is —CH₂—CH═CH—Ph, then Z¹⁰⁰ is not BOC;

when R² is H and R¹ is then Z¹⁰⁰ is not BOC;

when R² is H and R¹ is —CH₂—C(CH₃)═CH₂, then Z¹⁰⁰ is not BOC; and

when R² is phenyl and R¹ is —CH₃, then Z¹⁰⁰ is not CH₃C(O)—.

A group of compounds preferred among the foregoing group of compounds offormula (III), designated “CC Group”, are those compounds wherein w is 0or 1; n is 1;

Z¹⁰⁰ is BOC, methyl, benzyl or CBZ;

R¹ is hydrogen, —(CH₂)_(q)—(C₃-C₇)cycloalkyl, —(CH₂)_(t)—A¹ or(C₁-C₁₀)alkyl where the (C₁-C₁₀)alkyl and (C₃-C₇)cycloalkyl groups areoptionally substituted with 1 to 3 fluoro and A¹ in the definition of R¹is optionally substituted with 1 to 3 substituents independentlyselected from the group consisting of F, Cl, Me, OMe, CF₃, OCF₃ andOCF₂H;

R² is hydrogen, (C₁-C₈)alkyl, —(C₀-C₃)alkyl—(C₃-C₇)cycloalkyl, phenyl,or —(C₁-C₃)alkyl-phenyl where the alkyl and phenyl groups are optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of F, CF₃, OH and OMe.

A group of compounds preferred among the “CC Group” compounds,designated “DD Group”, contains those compounds of “CC Group” whereinZ¹⁰⁰ is BOC; w is 1; e is 0; R¹ is —CH₂—pyridyl, —CH₂—thiazolyl, or—CH₂—phenyl optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of fluoro and chloro;and R² is hydrogen, (C₂-C₄)alkyl or phenyl where the (C₁-C₄)alkyl orphenyl groups in the definition of R² is optionally substituted with 1to 3 substituents independently selected from the group consisting offluoro, hydroxy and methoxy.

Compounds which are preferred among the “DD Group” compounds is thediastereomeric mixture of a compound wherein R¹ is —CH₂—phenyl and R² ismethyl or hydrogen; and the separated 3a-(R) and 3a-(S) isomers arepreferred of the diastereomeric mixture.

Yet another group of compounds which are useful in the synthesis of thecompounds of formula (I) contains those compounds of the formula

the racemic-diastereomeric mixtures and optical isomers of saidcompounds wherein Z²⁰⁰ is t-BOC, CBZ, CF₃C(O)—, FMOC, TROC, trityl,tosyl or optionally substituted benzyl which is optionally substitutedwith methoxy, dimethoxy or nitro;

θ is 0 or 1;

n and w are each independently 0, 1 or 2, provided that w and n cannotboth be 0 at the same time;

Y is oxygen or sulfur;

R¹ is hydrogen, —CN, —(CH₂)_(q)N(X⁶)C(O)X⁶,—(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)SO₂(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)SO₂X⁶, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)C(O)OX⁶,—(CH₂)_(q)C(O)O(CH₂)_(t)—A¹, —(CH₂)_(q)OX⁶, —(CH₂)_(q)OC(O)X⁶,—(CH₂)_(q)OC(O)(CH₂)_(t)—A¹, —(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)OX⁶, —(CH₂)_(q)N(X⁶)SO₂N(X⁶)(X⁶),—(CH₂)_(q)S(O)_(m)X⁶, —(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹, —(C₁-C₁₀)alkyl,—(CH₂)_(t)—A¹, —(CH₂)_(q)—(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹—(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)—(C₃-C₇)cycloalkyl;

where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxyl, (C₁-C₄)alkoxy,carboxyl, CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl or 1 to 3 fluoro;

Y¹ is O, S(O)_(m), —C(O)NX⁶, —CH═CH—, —C≡C—, —N(X⁶)C(O), —C(O)NX⁶,—C(O)O, —OC(O)N(X⁶) or —OC(O);

q is 0, 1, 2, 3 or 4;

t is 0, 1, 2 or 3;

said (CH₂)_(q)group and (CH₂)_(t) group may each be optionallysubstituted with hydroxyl, (C₁-C₄)alkoxy, carboxyl, —CONH₂,—S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl, 1H-tetrazol-5-yl, 1 to 3 fluoroor 1 or 2 (C₁-C₄)alkyl;

R² is hydrogen, (C₁-C₈)alkyl, —C₀-C₃)alkyl—(C₃-C₈)cycloalkyl,—(C₁-C₄)alkyl—A¹ or A¹;

where the alkyl groups and the cycloalkyl groups in the definition of R²are optionally substituted with hydroxyl, —C(O)OX⁶, —C(O)N(X⁶)(X⁶),—N(X⁶(X⁶), —S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹, —C(O)(X⁶), CF₃, CN or 1 to 3halogen;

R³ is A¹, (C₁-C₁₀)alkyl, —(C₁-C₆)alkyl—A¹,—(C₁-C₈)alkyl—(C₃-C₇)cycloalkyl, —(C₁-C₅)alkyl—X¹—(C₁-C₅)alkyl,—(C₁-C₅)alkyl—X¹-(C₀-C₅)alkyl—A¹ or—(C₁-C₅)alkyl—X¹—(C₁-C₅)alkyl—(C₃-C₇)cycloalkyl;

where the alkyl groups in the definition of R³ is optionally substitutedwith —S(O)_(m)(C₁-C₆)alkyl, —C(O)CX³, 1 to 5 halogens or 1 to 3 OX³;

X¹ is O, S(O)_(m), —N(X²)C(O)—, —C(O)N(X²)—, —OC(O)—, —C(O)O—,—CX²═CX²—, —N(X²)C(O)O—, —OC(O)N(X²)—or —C≡C—;

R⁴ is hydrogen, (C₁-C₆)alkyl or (C₃-C₇)cycloalkyl, or R⁴ is takentogether with R³ and the carbon atom to which they are attached and form(C₅-C₇)cycloalkyl, (C₅-C₇)cycloalkenyl, a partially saturated or fullysaturated 4- to 8-membered ring having 1 to 4 heteroatoms independentlyselected from the group consisting of oxygen, sulfur and nitrogen, or isbicyclic ring system consisting of a partially saturated or fullysaturated 5- or 6-membered ring, fused to a partially saturated, fullyunsaturated or fully saturated 5- or 6-membered ring, optionally having1 to 4 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen;

X⁴ is hydrogen or (C₁-C₆)alkyl or X⁴ is taken together with R⁴ and thenitrogen atom to which X⁴ is attached and the carbon atom to which R⁴ isattached and form a five to seven membered ring;

R⁶ is a bond or is

where a and b are independently 0, 1, 2 or 3;

X⁵ and X^(5a) are each indenpendently selected from the group consistingof hydrogen, trifluoromethyl, A¹ and optionally substituted(C₁-C₆)alkyl;

the optionally substituted (C₁-C₆)alkyl in the definition of X⁵ andX^(5a) is optionally substituted with a substituent selected from thegroup consisting of A¹, —OX², —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX²,

(C₃-C₇)cycloalkyl, —N(X²)(X²) and —C(O)N(X²)(X²);

or the carbon bearing X⁵ and X^(5a) forms an alkylene bridge with thenitrogen atom bearing Z²⁰⁰ and R⁸ where the alkylene bridge contains 1to 5 carbon atoms provided that X⁵ and X^(5a) but not both may be on thecarbon atom and Z²⁰⁰ or R⁸ but not both may be on the nitrogen atom;

or X⁵ is taken together with X^(5a) and the carbon atom to which theyare attached and form a partially saturated or fully saturated 3- to7-membered ring, or a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen;

or X⁵ is taken together with X^(5a) and the carbon atom to which theyare attched and form a bicyclic ring system consisting of a partiallysaturated or fully saturated 5- to 6-membered ring, optionally having 1to 2 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen, fused to a partially saturated, fullysaturated or fully unsaturated 5- or 6- membered ring, optionally having1 to 4 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen;

Z¹ is a bond, O or N-X², provided that when a and b are both 0 then Z¹is not N-X² or O;

R⁸ is hydrogen or optionally substituted (C₁-C₆)alkyl;

where the optionally substituted (C₁-C₆)alkyl in the definition of R⁸ isoptionally independently substituted with A¹, —C(O)O—(C₁-C₆)alkyl,—S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3—O—C(O)(C₁-C₁₀)alkyl or 1 to 3 (C₁-C₆)alkoxy; or

A¹ for each occurence is independently (C₅-C₇)cycloalkenyl, phenyl or apartially saturated, fully saturated or fully unsaturated 4- to8-membered ring optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of oxygen, sulfur and nitrogen, orbicyclic ring system consisting of a partially saturated, fullyunsaturated or fully saturated 5- to 6-membered ring, optionally having1 to 4 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen, fused to a partially saturated, fullysaturated or fully unsaturated 5- to 6-membered ring, optionally having1 to 4 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen;

A¹ for each occurrence is independently optionally substituted, in oneor optionally both rings if A¹ is a bicyclic ring system, with up tothree substituents, each substituent independently selected from thegroup consisting of F, Cl, Br, I, ICF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶,—C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo, (C₁-C₆)alkyl, nitro, cyano, benzyl,—S(O)_(m)(C₁-C₆)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy,phenylalkyloxy, halophenyl, methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶),—SO₂N(X⁶)(X⁶), —N(X⁶)SO₂-phenyl, —N(X⁶)SO₂X⁶, —CONX¹¹X¹², —SO₂NX¹¹NX¹²,—NX⁶SO₂X¹², —NX⁶CONX¹¹X¹², —NX⁶SO₂NX¹¹X¹², —NX⁶C(O)X¹², imidazolyl,thiazolyl and tetrazolyl, provided that if A¹ is optionally substitutedwith methylenedioxy then it can only be substituted with onemethylenedioxy;

where X¹¹ is hydrogen or optionally sustituted (C₁-C₆)alkyl;

the optionally substituted (C₁-C₆)alkyl defined for X¹¹ is optionallyindependently substituted with phenyl, phenoxy, (C₁-C₆)alkoxycarbonyl,—S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3(C₁-C₁₀)alkanoyloxy or 1 to 3 (C₁-C₆)alkoxy;

X¹² is hydrogen, (C₁-C₆)alkyl, phenyl, thiazolyl, imidazolyl, furyl orthienyl, provided that when X¹² is not hydrogen, X¹² is optionallysubstituted with one to three substituents independently selected fromthe group consisting of Cl, F, CH₃, OCH₃, OCF₃ and CF₃;

or X¹¹ and X¹² are taken together to form —(CH₂)_(r)—L¹—(CH₂)_(r)—;

L¹ is C(X²)(X²), O, S(O)_(m) or N(X²);

r for each occurence is independently 1, 2 or 3;

X² for each occurrence is independently hydrogen, optionally substituted(C₁-C₆)alkyl, or optionally substituted (C₃-C₇)cycloalkyl, where theoptionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl in the definition of X² are optionally independentlysubstituted with —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halogens or 1to 3 —OX³;

X³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl;

X⁶ for each occurrence is independently hydrogen, optionally substituted(C₁-C₆)alkyl, (C₂-C₆)halogenated alkyl, optionally substituted(C₃-C₇)cycloalkyl, (C₃-C₇)—halogenatedcycloalkyl, where optionallysubstituted (C₁-C₆)alkyl and optionally substituted (C₃-C₇)cycloalkyl inthe definition of X⁶ is optionally independently substituted withhydroxyl, (C₁-C₄)alkoxy, carboxyl, CONH₂, —S(O)_(m)(C₁-C₆)alkyl,—CO₂(C₁-C₄)alkyl, 1H-tetrazol-5-yl or 1 or 2 (C₁-C₄)alkyl; or

when there are two X⁶ groups on one atom and both X⁶ are (C₁-C₆)alkyl,the two (C₁-C₆)alkyl groups may be optionally joined and, together withthe atom to which the two X⁶ groups are attached, form a 4- to9-membered ring optionally having oxygen, sulfur or NX⁷;

X⁷ is hydrogen or (C₁-C₆)alkyl optionally substituted by hydroxyl; and

m for each occurrence is independently 0, 1 or 2;

with the proviso that:

X⁶ and X¹² cannot be hydrogen when it is attached to C(O) or SO₂ in theform C(O)X⁶, C(O)X¹², SO₂X⁶ or SO₂X¹², and

when R⁶ is a bond then L is N(X²) and each r in the definition—(CH₂)_(r)—L—(CH₂)_(r)—is 2 or 3.

Compounds which are preferred of the foregoing compounds of formula (IV)is the compound wherein e is 0; Y is O; R¹ is —CH₂—phenyl; R² is methylor hydrogen; n is 1; w is 1; R³ is —CH₂—O—CH₂—phenyl; R⁴ is hydrogen; X⁴is hydrogen; R⁶ is —C(CH₃)₂—; Z²⁰⁰ is BOC and R⁸ is hydrogen. Thisinvention also provides:

a method for increasing levels of endogenous growth hormone in a humanor other animal which comprises administering to such human or otheranimal an effective amount of a compound of Formula I;

a pharmaceutical composition useful for increasing the endogenousproduction or release of growth hormone in a human or other animal whichcomprises an inert carrier and an effective amount of a compound ofFormula I;

a pharmaceutical composition useful for increasing the endogenousproduction or release of growth hormone in a human or other animal whichcomprises an inert carrier, an effective amount of a compound of FormalI and another growth hormone secretagogue such as, GHRP-6, Hexarelin,GHRP-1, IGF-1, IGF-2, B-HT920 or growth hormone releasing factor (GRF)or an analog thereof;

a method for the treatment or prevention of osteoporosis which comprisesadministering to a human or other animal in need of such treatment orprevention an amount of a compound of Formula I which is effective intreating or preventing osteoporosis;

a method for the treatment or prevention of osteoporosis which comprisesadministering to a human or other animal with osteoporosis a combinationof a bisphosphonate compound such as alendronate, and especiallypreferred is the bisphosphonate compound ibandronate, and a compound ofFormula I;

a method for the treatment or prevention of osteoporosis which comprisesadministering to a human or other animal with osteoporosis a combinationof estrogen or Premarin® and a compound of Formula I and optionallyprogesterone;

a method to increase IGF-1 levels in IGF-1 deficient humans or otheranimals which comprises administering to a human or other animal withIGF-1 deficiency a compound of Formula I;

a method for the treatment of osteoporosis which comprises administeringto a human or other animal with osteoporosis a combination of anestrogen against or antagonist such as tamoxifen, droloxifene,raloxifene and idoxifene and a compound of Formula I;

a particularly preferred method for the treatment of osteoporosiscomprises administering to a human or other animal with osteoporosis acombination of an estrogen agonist or antagonist such asCis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

(-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;

cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydro-naphthalene;

1-(4′-pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;or

1-(4′-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydro-isoquinolineand a compound of Formula I;

a method for the treatment of osteoporosis which comprises administeringto a human or other animal with osteoporosis a combination of calcitoninand a compound of Formula I;

a method for increasing muscle mass, which method comprisesadministering to a human or other animal in need of such treatment anamount of a compound of Formula I which is effective in promotingrelease of endogenous growth hormone; and

a method for promoting growth in growth hormone deficient children whichcomprises administering to a growth hormone deficient child a compoundof Formula I which is effective in promoting release of endogenousgrowth hormone.

This invention further provides a method for treating or preventingdiseases or conditions which may be treated or prevented by growthhormone which comprises administering to a human or other animal in needof such treatment or prevention an amount of a compound of Formula Iwhich is effective in promoting release of endogenous growth hormone.

In another aspect, this invention provides methods for treating orpreventing congestive heart failure, frality associated with aging, andobesity which comprise administering to human or other animal in need ofsuch treatment or prevention an amount of a compound of Formula I whichis effective in promoting release of endogenous growth hormone; of theinstant method it is preferred that the disease or condition to betreated or prevented is congestive heart failure or frality assoicatedwith aging.

In another aspect, this invention provides methods for accelerating bonefracture repair, attenuating protein catabolic response after a majoroperation, reducing cachexia and protein loss due to chronic illnesssuch as AIDS and cancer, accelerating wound healing, and acceleratingthe recovery of burn patients or patients having undergone majorsurgery, which comprise administering to a human or other animal in needof such treatment an amount of a compound of Formula I which iseffective in promoting release of endogenous growth hormone; of theinstant method a preferred method of use is to accelerate bone fracturerepair or for accelerating the recovery of patients having undergonemajor surgery.

In yet another aspect, this invention provides methods for improvingmuscle strength, mobility, maintenance of skin thickness, metabolichomeostasis and renal homostasis, which comprise administering to ahuman or other animal in need of such treatment an amount of a compoundof claim 1 which is effective in promoting release of endogenous growthhormone.

The instant compounds promote the release of growth hormone which arestable under various physiological conditions and may be administeredparenternally, nasally or by the oral route.

DETAILED DESCRIPTION OF THE INVENTION

One of ordinary skill will recognize that certain substituents listed inthis invention may have reduced chemical stability when combined withone another or with heteroatoms in the compounds. Such compounds withreduced chemical stability are not preferred.

In general the compounds of Formula I can be made by processes whichinclude processes known in the chemical arts for the production ofcompounds. Certain processes for the manufacture of Formula I compoundsare provided as further features of the invention and are illustrated bythe following reaction schemes.

In the above structural formulae and throughout the instant application,the following terms have the indicated meanings unless expressly statedotherwise:

The alkyl groups are intended to include those alkyl groups of thedesignated length in either a straight or branched configuration whichmay optionally contain double or triple bonds. Exemplary of such alkylgroups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, teritarybutyl, pentyl, isopentyl, hexyl, isohexyl, allyl, ethynyl, prophenyl,butadienyl, hexenyl and the like.

When the definition C₀-alkyl occurs in the definition, it means a singlecovalent bond.

The alkoxy groups specified above are intended to include those alkoxygroups of the designated length in either a straight or branchedconfiguration which may optionally contain double or triple bonds.Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobuoxy, tertiary butoxy, pentoxy, isopentoxy,hexoxy, isohexoxy, allyloxy, 2-propynyloxy, isobutenyloxy, hexenyloxyand the like.

The term “halogen” or “halo” is intended to include the halogen atomsfluorine, chlorine, bromine and iodine.

The term “halogenated alkyl” is intended to include an alkyl group asdefined hereinabove substituted by one or more halogen atoms as definedhereinabove.

The term “halogenated cycloalkyl” is intended to include a cycloalkylgroup substituted by one or more halogen atoms as defined hereinabove.

The term “aryl” is intended to include phenyl and naphthyl and aromatic5- and 6-membered rings with 1 to 4 heteroatoms or fused 5- or6-membered bicyclic rings with 1 to 4 heteroatoms of nitrogen, sulfur oroxygen. Examples of such heterocyclic aromatic rings are pyridine,thiophene (also known as thienyl), furan, benzothiophene, tetrazole,indole, N-methylindole, dihydroindole, indazole, N-formylindole,benzimidazole, thiazole, pyrimidine, and thiadiazole.

The chemist of ordinary skill will recognize that certain combinationsof heteroatom-containing substituents listed in this invention definecompounds which will be less stable under physiological conditions(e.g., those containing acetal or animal linkages). Accordingly, suchcompounds are less preferred.

The expression “prodrug” refers to compounds that are drug precursors,which following administration, release the drug in vivo via somechemical or physilogical process (e.g., a prodrug on being brought tothe physilogical pH is converted to the desired drug form). Exempleryprodrugs upon cleavage release the corresponding free acid, and suchhydrolyzable ester-forming residues of the compounds of this inventioninclude but are not limited to carboxylic acid substituents (e.g., R¹ is—(CH₂)_(q)C(O)₂X⁶ where X⁶ is hydrogen, or R² or A¹ contains carboxylicacid) wherein the free hydrogen is replaced by (C₁-C₄)alkyl,(C₂-C₁₂)alkanoyloxymethyl, (C₄-C₉)1-(alkanoyloxy)ethyl,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N-(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)-alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

Other exemplary prodrugs release an alcohol of Formula I wherein thefree hydrogen of the hydroxyl substituents (e.g., R¹ contains hydroxyl)is replaced by (C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N(C₁-C₆)alkoxy-carbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanoyl, arylacetyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl wherein said α-aminoacyl moieties areindependently any of the naturally occurring L-amino acids found inproteins, P(O)(OH)₂, —(P(O)(O(C₁-C₆)alkyl₂ or glycosyl (the radicalresulting from detachment of the hydroxyl of the hemiacetal of acarbohydrate).

Prodrugs of this invention where a carboxyl group in a carboxlic acid ofFormula (I) is replaced by an ester may be prepared by combining thecarboxylic acid with the appropriate alkyl halide in the presence of abase such as postassium carbonate in an inert solvent such as DMF at atemperature of about 0° C. to 100° C. for about 1 to about 24 hours.Alternatively, the acid is combined with the appropriate alcohol assolvent in the presence of a catalytic amount of acid such asconcentrated sulfuric acid at a temperature of about 20° C. to 120° C.,preferably at reflux, for about 1 hour to about 24 hours. Another methodis the reaction of the acid in an inert solvent such as THF, withconcomitant removal of the water being produced by physical (e.g., DeanStark trap) or chemical (e.g., molecular sieves) means.

Prodrugs of this invention where an alcohol function has beenderivatized as an ether may be prepared by combining the alcohol withthe appropriate alkyl bromide or iodide in the presence of a base suchas potassium carbonate in an inert solvent such as DMF at a temperatureof about 0° C. to 100° C. for about 1 to about 24 hours.Alkanoylaminomethyl ethers may be obtained by reaction of the alcoholwith a bis-(alkanoylamino)methane in the presence of a catalytic amountof acid in an inert solvent such as THF, according to a method describedin U.S. Pat. No. 4,997,984. Alternatively, these compounds may beprepared by the methods described by Hoffman et al. in J. Org. Chem.1994, 59, p. 3530.

Certain of the above defined terms may occur more than once in the aboveformula and upon such occurrence each term shall be definedindependently of the other.

Throughout the specification and appendent claims the followingabbreviations are used with the following meanings:

BOC t-butloxycarbonyl BOP Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate CBZ Benzloxycarbonyl CDIN,N′-Carbonyldiimidazole CH₂Cl₂ Methylene chloride CHCl₃ Chloroform DCCDicyclohexylcarbodiimide DMF Dimethylformamide EDC1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride EtOAc Ethylacetate FMOC 9-Fluorenylmethoxycarbonyl h hours Hex Hexane HOAT1-Hydroxy-7-azabenzotriazole HOBT Hydroxybenzotriazole hydrate HPLC Highpressure liquid chromatography MHz Megahertz MS Mass Spectrum NMRNuclear Magnetic Resonance PTH Parathyroid hormone TFA Trifluoroaceticacid THF Tetrahydrofuran TLC Thin layer chromatography TRH Thyrotropinreleasing hormone TROC 2,2,2-Trichloroethoxycarbonyl

The compounds of the instant invention all have at least one asymmetriccenter as noted by the asterisk in the structural Formula I, above.Additional asymmetric centers may be present on the molecule dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will produce two optical isomers and it is intendedthat all such optical isomers, as separated, pure or partially purifiedoptical isomers, racemic mixtures or diastereomeric mixtures thereof, beincluded within the scope of the instant invention. In the case of theasymmetric center represented by the asterisk, it has been found thatthat absolute stereochemistry of the more active and thus more preferredisomer is shown in Formula IA. This preferred absolute configurationalso applies to Formual I.

With the R⁴ substituents as hydrogen, the spatial configuration of theasymmetric center corresponds to that in a D-amino acid. In most casesthis is also designated an R-configuration although this will varyaccording to the values of R³ and R⁴ used in making R- orS-stereochemical assignments.

The instant compounds are generally isolated in the form of theirpharmaceutically acceptable acid addition salts, such as the saltsderived from using inorganic and organic acids. Examples of such acidsare hydrochloric, nitric, sulfuric, phosphoric, formic, acetic,trifluoroacetic, propionic, maleic, succinic, D-tartaric, L-tartaric,malonic, methane sulfonic and the like. In addition, certain compoundscontaining an acidic function such as a carboxy can be isolated in theform of their inorganic salt in which the counter-ion can be selectedfrom sodium, potassium, lithium, calcium, magnesium and the like, aswell as from organic bases.

The pharmaceutically acceptable salts are formed by taking about 1equivalent of a compound of formula (I) and contacting it with about 1equivalent of the appropriate corresponding acid of the salt which isdesired. Work-up and isolation of the resulting salt is well-known tothose of ordinary skill in the art.

The growth hormone releasing compounds of Formula I are useful in vitroas unique tools for understanding how growth hormone secretion isregulated at the pituitary level. This includes use in the evaluation ofmany factors thought or known to influence growth hormone secretion suchas age, sex, nutritional factors, glucose, amino acids, fatty acids, aswell as fasting and non-fasting states. In addition, the compounds ofthis invention can be used in the evaluation of how other hormonesmodify growth hormone releasing activity. For example, it has alreadybeen established that somatostatin inhibits growth hormone release.

The compounds of Formula I can be administered to animals, includinghumans, to release growth hormone in vivo. The compounds are useful fortreatment of symptoms related to GH deficiency; stimulate growth orenhance feed efficiency of animals raised for meat production to improvecarcass quality; to increase milk production in dairy cattle;improvement of bone or wound healing and improvement in vital organfunction. The compounds of the present invention by inducing endogenousGH secretion will alter body composition and modify other GH-dependentmetabolic, immunologic or developmental processes. For example, thecompounds of the present invention can be given to chickens, turkeys,livestock animals (such as sheep, pigs, horses, cattle, etc), companionanimals (e.g., dogs) or may have utility in aquaculture to accelerategrowth and improve the protein/fat ratio. In addition, these compoundscan be administered to humans in vivo as a diagnostic tool to directlydetermine whether the pituitary is capable of releasing growth hormone.For example, the compounds of Formula I can be administered in vivo tochildren. Serum samples taken before and after such administration canbe assayed for growth hormone. Comparison of the amounts of growthhormone in each of these samples would be a means for directlydetermining the ability of the patient's pituitary to release growthhormone.

Accordingly, the present invention includes within its scopepharmaceutical compositions comprising, as an active ingredient, atleast one of the compounds of Formula I in association with apharmaceutically acceptable carrier. Optionally, the pharmaceuticalcompositions can further comprise an anabolic agent in addition to atleast one of the compounds of Formula I or another compound whichexhibits a different activity, e.g., an antibiotic growth, permittant oran agent to treat osteoporosis or with other pharmaceutically activematerials wherein the combination enhances efficacy and minimizes sideeffects.

Growth promoting and anabolic agents include, but are not limited to,TRH, PTH, diethylstilbesterol, estrogens, β-agonists, theophylline,anabolic steroids, enkephalins, E series prostaglandins, compoundsdisclosed in U.S. Pat. No. 3,239,345, the disclosure of which is herebyincorporated by reference, e.g., zeranol; compounds disclosed in U.S.Pat. No. 4,036,979, the disclosure of which is hereby incorporated byreference, e.g., sulbenox; and peptides disclosed in U.S. Pat. No.4,411,890, the disclosure of which is hereby incorporated by reference.

The growth hormone secretagogues of this invention in combination withother growth hormone secretagogues such as the growth hormone releasingpeptides GHRP-6 and GHRP-1 as described in U.S. Pat. No. 4,411,890, thedisclosure of which is hereby incorporated by reference, andpublications WO 89/07110, WO 89/07111 and B-HT920 as well as hexarelinand the newly discovered GHRP-2 as described in WO 93/04081 or growthhormone releasing hormone (GHRH, also designated GRF) and its analogs orgrowth hormone and its analogs or somatomedins including IGF-1 and IGF-2or μ-adrenergic agonists such as clonidine or serotonin 5HTID agonistssuch as sumitriptan or agents which inhibit somatostatin or its releasesuch as physostigmine and pyridostigmine, are useful for increasing theendogenous levels of GH in mammals. The combination of a GH secretagogueof this invention with GRF results in synergistic increases ofendogenous growth hormone.

As is well known to those skilled in the art, the known and potentialuses of growth hormone are varied and multitudinous [See “Human GrowthHormone”, Strobel and Thomas, Pharmacological Reviews, 46, pg.1-34(1994); T. Rosen et al., Horm Res, 1995; 43: pp. 93-99; M. Degerbladet al., European Journal of Endocrinology, 1995, 133: pp. 180-188; J. O.Jorgensen, European Journal of Endocrinology, 1994, 130: pp. 224-228; K.C. Copeland et al., Journal of Clinical Endocrinology and Metabolism,Vol. 78 No. 5, pp. 1040-1047; J. A. Aloi et al., Journal of ClinicalEndocrinology and Metabolism, Vol. 79 No. 4, pp. 943-949; F. Cordido etal., Metab. Clin. Exp., (1995), 44(6), pp. 745-748; K. M. Fairhall etal., J. Endocrinol., (1985), 145(3), pp. 417-426; R. M. Frieboes et al.,Neuroendocrinology, (1995), 61(5), pp. 584-589; and M. Liovera et al.,Int. J. Cancer, (1995), 61(1), pp. 138-141]. Thus, the administration ofthe compounds of this invention for purposes of stimulating the releaseof endogenous growth hormone can have the same effects or uses as growthhormone itself. These varied uses of growth hormone may be summarized asfollows: stimulating growth hormone release in elderly humans; treatinggrowth hormone deficient adults; preventing catabolic side effects ofglucocorticoids, treating osteoporosis, stimulating the immune system,acceleration of wound healing, accelerating bone fracture repair,treating growth retardation, treating congestive heart failure asdisclosed in PCT publications WO 95/28173 and WO 95/28174 (an example ofa method for assaying growth hormone secretagogues for efficacy intreating congestive heart failure is disclosed in R. Yang et al.,Circulation, Vol. 92, No. 2, p.262, 1995), treating acute or chronicrenal failure or insufficiency, treatment of physiological shortstature, including growth hormone deficient children, treating shortstature associated with chronic illness, treating obesity, treatinggrowth retardation associated with Prader-Willi syndrome and Turner'ssyndrome; accelerating the recovery and reducing hospitalization of burnpatients or following major surgery such as gastrointestinal surgery;treating intrauterine growth retardation, skeletal dysplasia,hypercortisonism and Cushings syndrome; replacing growth hormone instressed patients; treating osteochondrodysplasias, Noonans syndrome,sleep disorders, Alzheimer's disease, delayed wound healing, andpsychosocial deprivation; treating of pulmonary dysfunction andventilator dependency; attentuating protein catabolic response after amajor operation; treating malabsorption syndromes, reducing cachexia andprotein loss due to chronic illness such as cancer or AIDS; acceleratingweight gain and protein accretion in patients on TPN (total parenteralnutrition); treating hyperinsulinemia including nesidioblastosis;adjuvant treatment for ovulation induction and to prevent and treatgastric and duodenal ulcers; stimulating thymic development andpreventing age-related decline of thymic function; adjunctive therapyfor patients on chronic hemodialysis; treating immunosuppressed patientsand enhancing antibody response following vaccination; improving musclestrength, increasing muscle mass, mobility, maintenance of skinthickness, metabolic homeostasis, renal hemeostasis in the frailelderly; stimulating osteoblasts, bone remodelling, and cartilagegrowth; treating neurological diseases such as peripheral and druginduced neuropathy, Guillian-Barre Syndrome, amyotrophic lateralsclerosis, multiple sclerosis, cerebrovascular accidents anddemyelinating diseases; stimulating the immune system in companionanimals and treating disorders of aging in companion animals; growthpromotant in livestock; and stimulating wool growth in sheep.

It will be known to those skilled in the art that there are numerouscompounds now being used in an effort to treat the diseases ortherapeutic indications enumerated above. Combinations of thesetherapeutic agents, some of which have also been mentioned above, withthe growth promotant, exhibit anabolic and desirable properties of thesevarious therapeutic agents. In these combinations, the therapeuticagents and the growth hormone secretagogues of this invention may beindependently and sequentially administered or co-administered in doseranges from one one-hundredth to one times the dose levels which areeffective when these compounds and secretagogues are used singly.Combined therapy to inhibit bone resorption, prevent osteoporosis,reduce skeletal fracture, enhance the healing of bone fractures,stimulate bone formation and increase bone mineral density can beeffectuated by combinations of bisphosphonates and the growth hormonesecretagogues of this invention, see PCT publication WO 95/11029 for adiscussion of combination therapy using bisphosphonates and GHsecretagogues. The use of bisphosphonates for these utilities has beenreviewed, for example, by Hamdy, N.A.T., Role of Bisphosphonates inMetabolic Bone Diseases, Trends in Endocrinol. Metab., 1993, 4, pages19-25. Bisphosphonates with these utilities include but are not limitedto alendronate, tiludronate, dimethyl-APD, risedronate, etidronate,YM-175, clodronate, pamidronate, and BM-210995 (ibandronate). Accordingto their potency, oral daily dosage levels of the bisphosphonate ofbetween 0.1 mg and 5 g and daily dosage levels of the growth hormonesecretagogues of this invention of between 0.01 mg/kg to 20 mg/kg ofbody weight are administered to patients to obtain effective treatmentof osteoporosis.

The compounds of this invention may be combined with a mammalianestrogen agonist/antagonist. Any estrogen agonist/antagonist may be usedas the second compound of this invention. The term estrogenagonist/antagonist refers to compounds which bind with the estrogenreceptor, inhibit bone turnover and prevent bone loss. In particular,estrogen agonists are herein defined as chemical compounds capable ofbinding to the estrogen receptor sites in mammalian tissue, andmimicking the actions of estrogen in one or more tissue. Estrogenantagonists are herein defined as chemical compounds capable of bindingto the estrogen receptor sites in mammalian tissue, and blocking theactions of estrogen in one or more tissues. Such activities are readilydetermined by those skilled in the art according to standard assaysincluding estrogen receptor binding assays, standard bonehistomorphometric and densitometer methods (see Eriksen E. F. et al.,Bone Histomorphometry, Raven Press, New York, 1994, pages 1-74; Grier S.J. et al., The Use of Dual-Energy X-Ray Absorptiometry In Animals, Inv.Radiol., 1996, 31(1):50-62; Wahner H. W. and Fogelman I., The Evaluationof Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice.,Martin Dunitz Ltd., London 1994, pages 1-296). A variety of thesecompounds are described and referenced below, however, other estrogenagonists/antagonists will be known to those skilled in the art. Apreferred estrogen agonist/antagonist is droloxifene: (phenol,3-[1-[4[2-(dimethylamino)ethoxy]-phenyl]-2-phenyl-1-butenyl]-,(E)-) andassociated compounds which are disclosed in U.S. Pat. No. 5,047,431 (thedisclosure of which is hereby incorporated by reference).

Another preferred estrogen agonist/antagonist is tamoxifen: (ethanamine,2-[-4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethyl,(Z)-2-,2-hydroxy-1,2,3-propanetricarboxylate(1:1)) and associated compounds which are disclosed in U.S. Pat. No.4,536,516 (the disclosure of which is hereby incorporated by reference).Another related compound is 4-hydroxy tamoxifen which is disclosed inU.S. Pat. No. 4,623,660 (the disclosure of which is hereby incorporatedby reference).

Another preferred estrogen agonist/antagonist is raloxifene: (methanone,[6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-hydrochloride)and associated compounds which are disclosed in U.S. Pat. No. 4,418,068(the disclosure of which is hereby incorporated by reference).

Another preferred estrogen agonist/antagonist is idoxifene: Pyrrolidine,1-[-[4-[[1-(4-iodophenyl)-2-phenyl-1-Butenyl]phenoxy]ethyl] andassociated compounds which are disclosed in U.S. Pat. No. 4,839,155 (thedistance of which is hereby incorporated by reference).

Other preferred estrogen agonist/antagonists include compounds asdescribed in commonly assigned U.S. Pat. No. 5,552,412 the disclosure ofwhich is hereby incorporated by reference. Especially preferredcomponents which are described therein are:

cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

(-)cis-6-phenyl-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

cis-6-phenyl-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4,-tetrahydronaphthalene;

1-(4′-pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;and

1-(4′-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline.

Other estrogen agonist/antagonists are described in U.S. Pat. No.4,133,814 (the disclosure of which is hereby incorporated by reference).U.S. Pat. No. 4,133,814 discloses derivatives of2-phenyl-3-aroyl-benzothiophene and2-phenyl-3-aroylbenzothiophene-1-oxide.

The following paragraphs provide preferred dosage ranges for variousanti-resorptive agents.

The amount of the anti-resorptive agent to be used is determined by itsactivity as a bone loss inhibiting agent. This activity is determined bymeans of an individual compound's pharmacokinetics and its minimalmaximal effective dose in inhibition of bone loss using a protocol suchas those reference above.

In general an effective dosage for the activities of this invention, forexample the treatment of osteoporosis, for the estrogenagonists/antagonists (when used in combination with a compound ofFormula I of this invention) is in the range of 0.01 to 200 mg/kg/day,preferably 0.5 to 100 mg/kg/day.

In particular, an effective dosage for droloxifene is in the range of0.1 to 40 mg/kg/day, preferably 0.1 to 5 mg/kg/day.

In particular, an effective dosage for raloxifene is in the range of 0.1to 100 mg/kg/day, preferably 0.1 to 10 mg/kg/day.

In particular, an effective dosage for tamoxifen is in the range of 0.1to 100 mg/kg/day, preferably 0.1 to 5 mg/kg/day.

In particular, an effective dosage for

cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

(-)cis-6-phenyl-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

cis-6-phenyl-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol;

cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4,-tetrahydronaphthalene;

1-(4′-pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;

cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;or

1-(4′-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolineis in the range of 0.0001 to 100 mg/kg/day, preferably 0.001 to 10mg/kg/day.

In particular, an effective dosage for 4-hydroxy tamoxifen is in therange of 0.0001 to 100 mg/kg/day, preferably 0.001 to 10 mg/kg/day.

Compounds that have the ability to stimulate GH secretion from culturedrat pituitary cells are identified using the following protocol. Thistest is also useful for comparison to standards to determine dosagelevels. Cells are isolated from pituitaries of 6-week old male Wistarrats. Following decapitation, the anterior pituitary lobes are removedinto cold, sterile Hank's balanced salt solution without calcium ormagnesium (HBSS). Tissues are finely minced, then subjected to twocycles of mechanically assisted enzymatic dispersion using 10 U/mLbacterial protease (EC 3.4.24.4, Sigma P-6141) in HBSS. Thetissue-enzyme mixture is stirred in a spinner flask at 30 rpm in a 5%CO₂ atmosphere at about 37° C. for about 30 min, with manual triturationafter about 15 min and about 30 min using a 10-mL pipet. This mixture iscentrifuged at 200×g for about 5 min. Horse serum is added to thesupernatant to neutralize excess protease. The pellet is resuspended infresh protease, stirred for about 30 min more under the previousconditions, and manually triturated, ultimately through a 23-gaugeneedle. Again, horse serum is added, then the cells from both digestsare combined, pelleted (200×g for about 15 min), washed, resuspended inculture medium and counted. Cells are plated at 6.0-6.5×10⁴ cells percm² in 48-well Costar dishes and cultured for 3-4 days in Dulbecco'sModified Eagle Medium (D-MEM) supplemented with 4.5 g/L glucose, 10%horse serum, 2.5% fetal bovine serum, 1% non-essential amino acids, 100U/mL nystatin and 50 mg/mL gentamycin sulfate before assaying for GHsecretion.

Just prior to assay, culture wells are rinsed twice, then equilibratedfor about 30 minutes in release medium (D-MEM buffered with 25 mM Hepes,pH 7.4 and containing 0.5% bovine serum albumin at 37° C.). Testcompounds are dissolved in DMSO, then diluted into pre-warmed releasemedium. Assays are run in quadruplicate. The assay is initiated byadding 0.5 mL of release medium (with vehicle or test compound) to eachculture well. Incubation is carried out at about 37° C. for about 15minutes, then terminated by removal of the culture medium, which iscentrifuged at 2000×g for about 15 minutes to remove cellular material.Rat growth hormone concentrations in the supernatants are determined bya standard radioimmunoassay protocol using a rat growth hormonereference preparation (NIDDK-rGH-RP-2) and rat growth hormone antiserumraised in monkey (NIDDK-anti-rGH-S-5) obtained from Dr. A. Parlow(Harbor-UCLA Medical Center, Torrence, Calif.). Additional rat growthhormone (1.5 U/mg. #G2414, Scripps Labs, San Diego, Calif.) is iodinatedto a specific activity of approximately 30 μCI/μg by the chloramine Tmethod for use as tracer. Immune complexes are obtained by adding goatantiserum to monkey IgG (Organon Teknika, Durham, N.C.) pluspolyethylene glycol, MW 10,000-20,000 to a final concentration of 4.3%;recovery is accomplished by centrifugation. This assay has a workingrange of 0.08-2.5 μg rat growth hormone per tube above basal levels.Active compounds typically stimulate growth hormone release by greaterthan 1.4 fold. Reference: Chang, K., Chan, W.-S., Barreto, Jr., A.,Convey, E. M., Smith, R. G. 1989.

Assay for Exogenously-Stimulated Growth Hormone Release in the Rat afterIntravenous Administration of Test Compounds

Twenty-one day old female Sprague-Dawley rats (Charles River Laboratory,Wilmington, Mass.) are allowed to acclimate to local vivanium conditions(24° C., 12 hr light, 12 hr dark cycle) for approximately 1 week beforecompound testing. All rats are allowed access to water and a pelletedcommercial diet (Agway Country Food, Syracuse, N.Y.) ad libitum. Theexperiments are conducted in accordance with the NIH Guide for the Careand Use of Laboratory Animals.

On the day of the experiment, test compounds are dissolved in vehiclecontaining 1% ethanol, 1 mM acetic acid and 0.1% bovine serum albumin insaline. Each compound is tested with n=3. Rats are weighed andanesthetized via intraperitoneal injection of sodium pentobarbital(Nembutol, 50 mg/kg body weight). Fourteen minutes after anestheticadministration, a blood sample is taken by nicking the tip of the tailand allowing the blood to drip into a microcentrifuge tube (baselineblood sample, approximately 100 μl). Fifteen minutes after anestheticadministration, test compound is delivered by intravenous injection intothe tail vein, with a total injection volume of 1 ml/kg body weight.Additional blood samples are taken from the tail at 5, 10 and 15 minutesafter compound administration. Blood samples are kept on ice until serumseparation by centrifugation (1430 xg for 10 minutes at 10° C.). Serumis stored at −80° C. until serum growth hormone determination byradio-immunoassay as described above and below.

Assessment of Exogenously-Stimulated Growth Hormone Release in the Dogafter Oral Administration

On the day of experimentation, the test compound is weighed out for theappropriate dose and dissolved in water. Doses are delivered at a volumeof 0.5 ml/kg by gavage to 4 dogs for each dosing regimen. Blood samples(2 ml) are collected from the jugular vein by direct vena puncturepre-dose and at 0.08, 0.17, 0.25, 0.5, 0.75, 1, 2, 4, 6, and 8 hourspost dose using 2 ml vacutainers containing lithium heparin. Theprepared plasma is stored at −20 C. until analysis.

Measurement of Canine Growth Hormone

Canine growth hormone concentrations are determined by a standardradioimmunoassay protocol using canine growth hormone (antigen foriodination and agents into the compositions, by irradiating thecompositions, or by heating the compositions. They can also bemanufactured in the form of sterile solid compositions which can bedissolved in sterile water, or some other sterile injectable mediumimmediately before use.

Compositions for rectal or vaginal administration are preferablysuppositories which may contain, in addition to the active substance,excipients such as coca butter or a suppository wax.

Compositions for nasal or sublingual administration are also preparedwith standard excipients well known in the art.

The dosage of active ingredient in the compositions of this inventionmay be varied; however, it is necessary that the amount of the activeingredient be such that a suitable dosage form is obtained. The selecteddosage depends upon the desired therapeutic effect, on the route ofadministration, and on the duration of the treatment. Generally, dosagelevels of between 0.0001 to 100 mg/kg of body weight daily areadministered to humans and other animals, e.g., mammals, to obtaineffective release of growth hormone.

A preferred dosage range is 0.001 to 5.0 mg/kg of body weight dailywhich can be administered as a single dose or divided into multipledoses.

The preparation of the compounds of Formula I of the present inventioncan be carried out in sequential or convergent synthetic routes.Syntheses detailing the preparation of the compounds of Formula I in asequential manner are presented in the reaction schemes shownhereinbelow.

Many protected amino acid derivatives are commercially available, wherethe protecting groups Prt, Z¹⁰⁰ and Z²⁰⁰ are, for example, BOC, CBZ,benzyl, ethoxycarbonyl groups, CF₃C(O)—, FMOC, TROC, trityl or tosyl.Other protected amino acid derivatives can be prepared by literaturemethods. Some 3-oxo-2-carboxyl pyrrolidines, and 4-oxo-3-carboxylpiperidines are commercially available, and many other relatedpyrrolidines and 4-substituted piperidines are known in the literature.

Many of the schemes illustrated below describe compounds which containprotecting groups Prt, Z¹⁰⁰ or Z²⁰⁰. Benzyloxycarbonyl groups can beremoved by a number of methods including, catalytic hydrogenation withhydrogen in the presence of a palladium or platinum catalyst in a proticsolvent such as methanol. Preferred reference preparation AFP-1983B) andcanine growth hormone antiserum raised in monkey (AFP-21452578) obtainedfrom Dr. A. Parlow (Harbor-UCLA Medical Center, Torrence, Calif.).Tracer is produced by chloramine T-iodination of canine growth hormoneto a specific activity of 20-40 μCi/μg. Immune complex are obtained byadding goat antiserum to monkey IgG (Organon Teknika, Durham, N.C.) pluspolyethylene glycol, MW 10,000-20,000 to a final concentration of 4.3%;recovery is accomplished by centrifugation. This assay has a workingrange of 0.08-2.5 μg canine GH/tube.

The compounds of this invention can be administered by oral, parenteral(e.g., intramuscular, intraperitoneal, intravenous or subcutaneousinjection, or implant), nasal, vaginal, rectal, sublingual, or topicalroutes of administration and can be formulated with pharmaceuticallyacceptable carriers to provide dosage forms appropriate for each routeof administration.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound is admixed with at least one inert pharmaceutically acceptablecarrier such as sucrose, lactose, or starch. Such dosage forms can alsocomprise, as is normal practice, additional substances other than suchinert diluents, e.g., lubricating agents such as magnesium stearate. Inthe case of capsules, tablets and pills, the dosage forms may alsocomprise buffering agents. Tablets and pills can additionally beprepared with enteric coatings.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, the elixirscontaining inert diluents commonly used in the art, such as water.Besides such inert diluents, compositions can also include adjuvants,such as wetting agents, emulsifying and suspending agents, andsweetening, flavoring and perfuming agents.

Preparations according to this invention for parenteral administrationinclude sterile aqueous or non-aqueous solutions, suspensions, oremulsions. Examples of non-aqueous solvents or vehicles are propyleneglycol, polyethylene glycol, vegetable oils, such as olive oil and cornoil, gelatin, and injectable organic esters such as ethyl oleate. Suchdosage forms may also contain adjuvants such as preserving, wetting,emulsifying, and dispersing agents. They may be sterilized by, forexample, filtration through a bacteria-retaining filter, byincorporating sterilizing catalysts are palladium hydroxide on carbon orpalladium on carbon. Hydrogen pressures from 1-1000 psi may be employed;pressures from 10 to 70 psi are preferred. Alternatively, thebenzyloxycarbonyl group can be removed by transfer hydrogenation.

Removal of BOC protecting groups can be carried out using a strong acidsuch as trifluoroacetic acid or hydrochloric acid with or without thepresence of a cosolvent such as dichloromethane, ethyl acetate, ether ormethanol at a temperature of about −30 to 70° C., preferably about −5 toabout 35° C.

Benzyl esters of amines can be removed by a number of methods including,catalytic hydrogenation with hydrogen in the presence of a palladiumcatalyst in a protic solvent such as methanol. Hydrogen pressures from1-1000 psi may be employed; pressures from 10 to 70 psi are preferred.The addition and removal of these and other protecting groups arediscussed by T. Greene in Protective Groups in Organic Synthesis, JohnWiley & Sons, New York, 1981.

SCHEME 1: The protected amino acid derivatives 1 are in many casescommercially available, where the protecting group Prt is, for example,BOC, FMOC or CBZ groups. Other amino acids can be prepared by literaturemethods.

As illustrated in Scheme 1, coupling of amines of formula 2 withprotected amino acids of formula 1, where Prt is a suitable protectinggroup, is conveniently carried out in an inert solvent such asdichloromethane or DMF by a coupling reagent such as EDC or DCC in thepresence of HOBT or HOAT. In the case where the amine is present as thehydrochloride salt, it is preferable to add one or two equivalents of asuitable base such as triethylamine to the reaction mixture.Alternatively, the coupling can be effected with a coupling reagent suchas BOP in an inert solvent such as methanol. Such coupling reactions aregenerally conducted at temperatures of about −30° to about 80° C.,preferably −10° to about 25° C. For a discussion of other conditionsused for coupling peptides see Houben-Weyl, Vol. XV, part II, E. Wunsch,Ed., George Theime Verlag, 1974, Stuttgart. Separation of unwanted sideproducts and purification of intermediates is achieved by chromatographyon silica gel, employing flash chromatography (W. C. Still, M. Kahn andA. Mitra, J. Org. Chem. 43 2923 1978), by crystallization or bytrituration.

Transformation of the compound of formula 3 into intermediates offormula 4 can be carried out by removal of the protecting group Prt asdescribed above. Coupling of intermediates of formula 4 to amino acidsof formula 5 can be effected as described above to give intermediates offormula 6. Deprotection of the amine 6 affords compounds of formula 7.

SCHEME 2: Alternatively, compounds of formula 7 can be prepared by aconvergent route as shown in Scheme 2. Intermediate esters of formula 8can be prepared by treating amino acids 1, where Prt is a suitableprotecting group, with a base such as potassium carbonate followed by analkyl halide such as iodomethane in a suitable solvent such as DMF.Deprotection of the amine transforms 8 into 9. Alternatively, many aminoacids of formula 9 are commercially available. Intermediate 10 isgenerated by coupling 9 to amino acid 5. The ester of intermediate 10can be converted to intermediate acid 11 by a number of methods known inthe art; for example, methyl and ethyl esters can be hydrolyzed withlithium hydroxide in a protic solvent such as aqueous methanol oraqueous THF at a temperature of about −20° to 120° C., preferably about0° to 50° C. In addition, removal of a benzyl group can be accomplishedby a number of reductive methods including hydrogenation in the presenceof platinum or palladium catalyst in a protic solvent such as methanol.Acid 11 can then be coupled to amine 2 to give intermediates of formula6. Transformation of 6 to 7 can be achieved by removal of the protectinggroup Z²⁰⁰.

SCHEME 3: The esters of formula 6 can be converted to intermediate acidsof formula 13 by a number of methods known in the art; for example,methyl and ethyl esters can be hydrolyzed with lithium hydroxide in aprotic solvent such as aqueous methanol or aqueous THF at a temperatureof about −20° to 120° C., preferably about 0° to 50° C. In addition,removal of a benzyl group can be accomplished by a number of reductivemethods including hydrogenation in the presence of platinum or palladiumcatalyst in a protic solvent such as methanol. Coupling the acid 13 toamine 16 generates the intermediates of formula 14. Transformation of 14to 15 can be achieved by removal of the protecting group Z²⁰⁰.

SCHEME 4: Esters of formula 17 can be prepared by treating an acid offormula 5 with hydroxysuccinimide in the presence of a coupling agentsuch as EDC in an inert solvent such as methylene chloride asillustrated in Scheme 4. Treatment of an ester 17 with an amino offormula 1 in a solvent such as dioxane, THF or DMF in the presence of abase such as diisoproplethylamine produces 11.

SCHEME 5: As illustrated in Scheme 5, alkylation of thediphenyloxazinone of formula 18 with cinnamyl bromide in the presence ofsodium bis(trimethylsilyl)amide generates 19 which is then converted tothe desired (D)-2-amino-5-phenylpentanoic acid 20 by removing theprotecting group (Prt) and hydrogenation over a PdCl₂ catalyst.

SCHEME 6: Treatment of an ester of formula 21 with a base such as sodiumhydride in a solvent such as DMF followed by an alkyl halide 22generates a compound of formula 23 as illustrated in Scheme 6. Treatinga compound of formula 23 with a hydrazine of formula 24 such ashydrazine or methyl-hydrazine in a solvent such as refluxing ethanol,followed by concentration and heating the residue in toluene attemperatures at or near reflux results in a compound of formula 25.Alternatively, 23 can be treated with a salt of a hydrazine in thepresence of sodium acetate in refluxing ethanol to give 25. Deprotectionof the amine generates a compound of formula 28. Thioamides of formula26 can be formed by treating 25 with Lawesson's reagent in refluxingtoluene or benzene. Removal of the protecting group transforms 26 into27.

SCHEME 7: Treatment of a compound of formula 21 with a hydrazine offormula 24 in a solvent such as refluxing ethanol, followed byconcentration and heating the residue in toluene at temperatures at ornear reflux results in compounds of formula 29. Alternatively, 21 can betreated with a salt of hydrazine in the presence of sodium acetate inrefluxing ethanol to give 29. The amide of formula 29 can be treatedwith a base such as sodium hydride in a solvent such as DMF followed byan alkyl halide to give 25. Deprotection of the amine generates acompound of formula 28.

SCHEME 8: Reaction of ketoester of formula 30 with a chiral amine suchas alpha-methylbenzylamine with a suitable aldehyde such asformaldehyde, or reaction of a vinyl ketoester of formula 31 with achiral amine such as alpha-methylbenzylamine with a suitable aldehydesuch as formaldehyde, affords a compound of formula 32 via a doubleMannich reaction. Reaction of 32 with a hydrazine generates a chiralcompound of formula 33. Deprotection of the nitrogen with hydrogen and asuitable catalyst such as palladium affords compounds of formula 34.

SCHEME 9: Treatment of a compound of formula 81 with a reducing agentsuch as sodium borohydride and protection of the nitrogen affords acompound of formula 82. Protection of the alcohol affords 83.Saponification of the ester affords a compound of formula 84. Reactionof 84 with thionyl chloride followed by treatment with diazomethaneaffords the homologated acid of formula 85. Esterification of 85 affordsa compound of formula 86, which is O-deprotected to give 87. Oxidationof 87 affords a ketone of formula 88. Reaction of 88 with a hydrazine,followed by nitrogen deprotection affords a compound of formula 44.

SCHEME 10: Treatment of a compound of formula 35 with a base such assodium hydride in a solvent such as DMF followed by treatment withdiethylcarbonate generates the ethyl ester of compound 36. Deprotectionof the amine transforms 36 into 37.

SCHEME 11: Treatment of a malonic ester of formula 38 with a base suchas sodium hydride in a solvent such a DMF and subsequent hydrogenolysisof the benzyl group with hydrogen and a catalyst such as palladium in asuitable solvent such as methanol produces the ester of formula 39.Deprotection of the amine generates compounds of formula 40.

SCHEME 12: Treatment of a ketone of formula 41 with a secondary aminesuch as piperidine in a suitable solvent such as benzene with removal ofwater affords an enamine of formula 42. Alkylation of the enamine withan alpha-haloester such as ethylbromoacetate in a suitable solvent suchas benzene or THF using a suitable base such as LDA or NaN(SiMe₃)₂affords a ketoester of formula 43. Reaction with a hydrazine of formula24 affords the compound of formula 44. Deprotection of the nitrogenaffords compounds of formula 45.

Scheme 13: Treatment of ketoester of formula 37 with an iodonium saltsuch as diphenyliodonium trifluoroacetate in a suitable solvent such ast-butanol generates a ketoester of formula 46. Reaction of 46 with ahydrazine generates a compound of formula 47. Deprotection of thenitrogen affords compounds of formula 48, see Synthesis, (9), 1984 p.709 for a detailed description.

SCHEME 14: Treatment of a ketoester of formula 37 with an olefin such asacrylonitrile generates a ketoester of formula 49. Reaction of 49 with ahydrazine generates a compound of formula 50. Deprotection of thenitrogen affords compounds of formula 51.

SCHEME 15: Treatment of a ketoester of formula 37 with allyl bromide anda suitable base such as sodium hydride in a suitable solvent such as DMFaffords a ketoester of formula 52. Reaction of 52 with a hydrazinegenerates a compound of formula 53. Oxonolysis of 53 in a suitablesolvent such as methylene chloride followed by treatment with a reducingagent such as dimethylsulfide affords an aldehyde of formula 54.Oxidation of 54 affords a carboxylic acid of formula 55. Curtisrearrangement of 55, followed by hydrolysis of the intermediateisocyanate affords a primary amine of formula 56. Treatment of acompound of formula 56 with an isocyanate or carbamate affords a urea offormula 57. Deprotection of the nitrogen affords compounds of formula58.

SCHEME 16: Treatment of a compound of formula 54 with a primary amineaffords an imine of formula 59. Reduction of a compound of formula 59affords a compound of formula 60. Treatment of a compound of formula 60with an acylating agent affords a compound of formula 61. Deprotectionof the nitrogen affords compounds of formula 62.

SCHEME 17: Treatment of a compound of formula 54 with a reducing agentsuch as sodium borohydride affords a compound of formula 63. Reaction of63 with an acylating agent such as an isocyanate of carbamate affordscompounds of formula 64. Deprotection of the nitrogen affords compoundsof formula 65.

SCHEME 18: Treatment of a compound of formula 63 with a phosphine suchas triphenyl phosphine and an azo compound such asdiethylazodicarboxylate and an oxindole affords a compound of formula66. Deprotection of the nitrogen affords the compound of formula 67.

SCHEME 19: Treatment of a ketoester of formula 37 with a chiral diol andacid catalyst with removal of water in a suitable solvent such asbenzene affords a chiral ketal of formula 68. Alkylation of 68 with analkyl halide in the presence of a base such as LDA followed byacid-catalyzed hydrolysis of the ketal affords chiral ketoesters offormula 69. Reaction of 69 with a hydrazine generates chiral compoundsof formula 70. Deprotection of the nitrogen affords compounds of formula71.

SCHEME 20: Treatment of ketoester of formula 37 with a chiral amino acidester such as valine t-butyl ester affords a chiral enamine of formula72. Alkylation of 72 with an alkyl halide in the presence of a base suchas LDA followed by acid-catalyzed catalyzed hydrolysis of the enamineaffords chiral ketoesters of formula 69. Reaction of 69 with a hydrazinegenerates chiral compounds of formula 70. Deprotection of the nitrogenaffords compounds of formula 71.

SCHEME 21: Deprotection of the nitrogen of 25 affords compounds offormula 28. Salt formation of 28 with a chiral acid affords a mixture ofdiastereomeric salts of formula 73. Crystallization of thediastereomeric salts affords the acid salt of chiral compounds offormula 70. Decomposition of the salt 70 with base liberates chiralcompounds of formula 71.

SCHEME 22: Alkylation of compounds of formula 25 with an allylic acetatein the presence of a suitable catalyst such as palladiumtetrakis(triphenylphosphine) affords compounds of formula 74.Deprotection of the nitrogen affords compounds of formula 75, seeTetrahedron (50) p. 515, 1994 for a detailed discussion.

SCHEME 23: Treatment of ketodiester of formula 76 with an alkyl halidein the presence of a base such as sodium hydride followed byacid-catalyzed hydrolysis and decarboxylation, followed byesterification with methyliodide and a suitable base affords a compoundof formula 77. Reaction of a compound of formula 77 with a suitablealdehyde such as formaldehyde and benzylamine affords a compound offormula 78. Reaction of compound of formula 78 with a hydrazinegenerates chiral compounds of formula 79. Deprotection of the nitrogenaffords compounds of formula 80.

SCHEME 24: Treatment of an amine of formula 23 with an acid of formula11 in an inert solvent such as dichloromethane or DMF by a couplingreagent such as EDC or DCC in the presence of HOBT affords compound offormula 89. Reaction of compounds of formula 89 with a hydrazinegenerates compounds of formula 6. Deprotection of the nitrogen affordscompounds of formula 7.

SCHEME 25: Treatment of hydroxyacetoacetate ester of formula 90 with analkyl halide in the presence of a suitable base such as sodium hydrideaffords compounds of formula 91. Reaction of 91 with a hydrazinegenerates compounds of formula 92. O-Alkylation of the carbonyl oxygenof 92 affords 93 which is converted to the halide 94. Displacement ofthe halide X by cyanide ion affords the nitrile 95. Reduction of 95gives the primary amine 96 which is deprotected and cyclized in thepresence of formaldehyde to afford 28.

SCHEME 26: Treatment of beta-keto-protected aminovalerate such as 97with an alkyl halide in the presence of a suitable base such as sodiumhydride affords compounds of formula 98. Reaction of compounds offormula 98 with a hydrazine generates compounds of formula 99.Deprotection of compounds of formula 99 affords primary amines offormula 100. Cyclization of compounds of formula 100 in the presence offormaldehyde affords compounds of formula 28.

SCHEME 27: Treatment of the amine of formula 23a with an acid such as 1in the presence of EDC of HOAT in a suitable solvent providesketo-esters of formula 23b. The keto-ester 23b can be treated with asalt of hydrazine in the presence of sodium acetate in refluxing ethanolto give hydrazines of formula 23c. Deprotection under suitableconditions gives amines of formula 4. Coupling of intermediates offormula 4 to amino acids of formula 5 can be effected as described aboveto give intermediates of formula 6. Deprotection of amine 6 affordscompounds of formula 7.

The following examples are provided for the purpose of furtherillustration only and are not intended to be limitations on thedisclosed invention.

General Experimental Procedures:

Amicon silica 30 μM, 60 Å pore size, was used for column chromatography.Melting points were taken on a Buchi 510 apparatus and are uncorrected.Proton and carbon NMR spectra were recorded on a Varian XL-300, BrukerAC-300, Varian Unity 400 or Bruker AC-250 at 25° C. Chemical shifts areexpressed in parts per million down field from trimethylsilane. Particlebeam mass spectra were obtained on a Hewlett-Packard 5989A spectrometerusing ammonia as the source of chemical ionization. For initial sampledissolution, chloroform or methanol was employed. Liquid secondary ionmass spectra (LSIMS) were obtained on a Kratos Concept-1S highresolution spectrometer using cesium ion bombardment on a sampledissolved in a 1:5 mixture of dithioerythritol and dithiothreitol or ina thioglycerol matrix. For initial sample dissolution chloroform ormethanol was employed. Reported data are sums of 3-20 scans calibratedcesium iodide. TLC analyses were performed using E. Merck Kieselgel 60F254 silica plates visualized (after elution with the indicatedsolvent(s)) by staining with 15% ethanolic phosphomolybdic acid andheating on a hot plate.

General Procedure A (Peptide coupling using EDC): A 0.2-0.5 M solutionof the primary amine (1.0 equivalent) in dichloromethane (or a primaryamine hydrochloride and 1.0-1.3 equivalents of triethylamine) is treatedsequentially with 1.0-1.2 equivalents of the carboxylic acid couplingpartner, 1.5-1.8 equivalents hydroxybenzotriazole hydrate (HOBT) or HOATand 1.0-1.2 equivalents (stoichiometrically equivalent to the quantityof carboxylic acid) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC) and the mixture is stirred overnight in an ice bath(the ice bath is allowed to warm, thus the reaction mixture is typicallyheld at about 0-20° C. for about 4-6 h and about 20-25° C. for theremaining period). The mixture is diluted with ethyl acetate or othersolvent as specified, and the resulting mixture washed twice with 1NNaOH, twice with 1N HCl (if the product is not basic), once with brine,dried over Na₂SO₄, and concentrated giving the crude product which ispurified as specified. The carboxylic acid component can be used as thedicyclohexylamine salt in coupling to the primary amine or hydrochlorideof the latter; in this case no triethylamine is employed.

EXAMPLE 12-Amino-N-{1(R)-benzyloxymethyl-2-[3a-(R)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-oxo-ethyl}-isobutyramidehyrochloride and2-Amino-N-{1(R)-benzyloxymethyl-2-[3a-(S)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-oxo-ethyl}-isobutyramidehydrochloride

A. 4-Oxo-Piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethylester

A mixture of 8.00 g (38.5 mmol) of 4-oxo-piperidine-3-carboxylic acidethyl ester hydrochloride, 9.23 g (42.4 mmol) ofdi-tert-butyldicarbonate, and 3.89 g (38.5 mmol) of triethylamine in 150mL of THF was stirred at room temperature for about 72 h. The mixturewas concentrated and the residue was dissolved in ethyl acetate andwashed three times each with 10% aqueous HCl, saturated aqueous sodiumbicarbonate solution, and brine, dried over MgSO₄, and concentrated togive 10.0 g of 1A as a white solid. MS (Cl, NH₃) 272 (MH⁺).

B. 3-(R,S)-(4-Fluoro-benzyl)-4-oxo-piperidine-1,3-dicarboxylic acid1-tert butyl ester 3-ethyl ester

To a solution of 2.00 g (7.4 mmol) 1A in 10 mL of DMF was added 282 mg(7.4 mmol) of sodium hydride (60% oil dispersion) and the mixture wasstirred at room temperature for about 15 min. A solution of 1.39 g (7.4mmol) 4-fluorobenzyl bromide in 7 mL of DMF was added to the stirringsolution and the mixture was stirred for about 72 h at room temperature.The mixture was diluted with ethyl acetate and washed once with waterand four times with brine, dried over MgSO₄, and concentrated to give2.8 g of 1B. MS (Cl, NH₃) 380 (MH⁺).

C.3a-(R,S)-(4-Fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

A mixture of 2.54 g (6.7 mmol) of 1B and 309 mg (6.7 mmol) ofmethylhydrazine in 100 mL of ethanol was heated at reflux for about 8 h.The mixture was concentrated and the residue was dissolved in 100 mLtoluene and heated at reflux for about 17 h. The mixture wasconcentrated and the residue was purified by silica gel chromatographyusing an elution gradient of (18:82 v/v ethyl acetate:hexane) to (75:25v/v ethyl acetate:hexane) to give 1.0 g of 1C as a clear colorless oil.MS (Cl, NH₃) 362 (MH⁺).

D.3a-(R,S)-(4-Fluoro-benzyl)-2-methyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-onetrifluoroacetate

To 1.00 g (2.8 mmol) of 1C was added 10 mL of trifluoroacetic acid atabout 0° C. and the mixture was stirred for about 1 h. Ethyl acetate wasadded and the mixture was concentrated to give 1.0 g of 1D. MS (Cl, NH₃)263 (MH⁺).

E.(R)-3-Benzyloxy-2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-propionicacid

To 1.83 g (6.2 mmol of N-t-BOC-O-benzyl-D-serine in 35 mL of DMF wasadded 1.02 g (7.4 mmol) of potassium carbonate followed by 0.92 g (6.5mmol) of iodomethane. The mixture was stirred overnight at about 24° C.under an atmosphere of nitrogen. The reaction mixture was diluted with200 mL of water, and extracted three times with ethyl acetate. Thecombined organics were washed five times with water and once with brine,dried over MgSO₄ and concentrated. The crude(R)-3-benzyloxy-2-tert-butoxycarbonyl-amino-propionic acid methyl esterwas dissolved in 15 mL of cold trifluoroacetic acid at about 0° C. andthe mixture was stirred for about 2 h. The mixture was concentrated andthe residue was diluted with 1N NaOH and extracted three times withethyl acetate. The combined organic extracts were washed with brine anddried over Na₂SO₄ to give 0.84 g (4.02 mmol) of the resulting(R)-2-amino-3-benzyloxy-propionic acid methyl ester which was coupled to0.81 g (4.02 mmol) of N-t-BOC-α-methylalanine to give 1.80 g of(R)-3-benzyloxy-2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-propionicacid methyl ester. The crude product was dissolved in 20 mL of 4:1THF:water and a solution of 335 mg (7.98 mmol) of lithium hydroxidehydrate in 1 mL of water was added to the solution and the mixture wasstirred overnight at room temperature. The mixture was concentrated andthe residue was diluted with ethyl acetate and acidified with aqueousHCl and extracted three times with ethyl acetate. The organic extractswere combined and washed once with brine, dried over Na₂SO₄ andconcentrated to give 1.60 g of 1E as an oil which solidified onstanding. ¹H NMR (CDCl₃ 300 MHz) δ 7.30 (m, 5H), 7.10 (d, 1H), 5.07 (bs,1H), 4.68 (m, 1H), 4.53 (q, 2H) 4.09 (m, 1H), 3.68 (m, 1H), 1.3-1.5 (m,15H).

F.(1-{1(R)-Benzyloxymethyl-2-[3a-(R,S)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-oxo-ethylcarbamoyl}-1-methyl-ethyl)-carbamicacid tert-butyl ester

According to the method outlined in General Procedure A, 193 mg (0.51mmol) of 1D and 196 mg (0.51 mmol) of 1E were coupled to give a mixtureof diastereomers. The residue was purified by silica gel chromatographyusing an elution gradient of (1:1 v/v ethyl acetate:hexane) to 100%ethyl acetate to give 60 mg of less polar 1F isomer 1 and 100 mg of morepolar 1F isomer 2. MS (Cl, NH₃) 624 (MH⁺) for both isomers.

G.2-Amino-N-{1(R)-benzyloxymethyl-2-[3a-(R)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-oxo-ethyl}-isobutyramidehydrochloride

To 60 mg (0.10 mmol) of 1F isomer 1 in 10 mL of ethanol was added 4 mLof concentrated HCl and the mixture was stirred at room temperature forabout 2 h. The mixture was concentrated and the residue was precipitatedfrom ethanol/hexane to give 50 mg of 1G isomer 1 as a white powder. MS(Cl, NH₃) 524 (MH⁺). ¹HNMR (CD₃OD): (partial) δ 7.32 (m, 5 H), 7.12 (m,2 H), 6.91 (m, 2 H), 5.15 (m, 1 H), 4.54 (s, 2 H), 3.78 (m, 2 H)3.02 (m,7 H), 2.66 (m, 2 H), 1.57 (s, 6 H).

H.2-Amino-N-{1(R)-benzyloxymethyl-2-[3a-(S)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-oxo-ethyl}-isobutyramidehydrochloride

To 100 mg (0.16 mmol) of 1F isomer 2 in 10 mL of ethanol was added 4 mLof concentrated HCl and the mixture was stirred at room temperature forabout 2 h. The mixture was concentrated and the residue was precipitatedfrom ethanol/hexane to give 60 mg of 1H isomer 2 as a white powder. MS(Cl, NH₃) 524 (MH⁺). ¹HNMR (CD₃OD): (partial) δ 7.32 (m, 5 H), 7.08 (m,2 H), 6.95 (m, 2 H), 6.80 (m, 2 H), 5.30 (m, 1 H), 4.61 (m, 3 H), 3.80(m, 2 H), 2.58 (m, 3 H), 1.58 (s, 6 H).

EXAMPLE 22-Amino-N-[2-[3a-(R,S)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-1(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramidehydrochloride

A. (R)-2-Amino-3-[(1H-indol-3-yl)-propionic acid methyl ester

To 4.92 g (16.2 mmol) of N-α-t-BOC-D-tryptophan in 100 mL of DMF wasadded 2.46 g (17.8 mmol) of potassium carbonate followed by 2.41 g (17.0mmol) of iodomethane, and the mixture was stirred overnight at 24° C.under an atmosphere of nitrogen. The reaction mixture was diluted withwater, and extracted three times with ethyl acetate. The combinedorganics were washed five times with 500 mL of water and once withbrine, dried over MgSO₄ and concentrated to give 4.67 g of a whitesolid. To the crude(R)-2-tert-butoxycarbonylamino-3-(1H-indol-3-yl)-propionic acid methylester was added 15 mL of cold trifluoroacetic acid at about 0° C. andthe mixture was stirred for about 2 h. The mixture was concentrated andthe residue was diluted with 1N NaOH and extracted three times withethyl acetate. The combined organic extracts were washed with brine anddried over Na₂SO₄ to give (R)-2-amino-3-(1H-indol-3-yl)-propionic acidmethyl ester as an orange oil in quantitative yield.

B.(R)-2-(2-tert-Butoxycarbonylamino-2-methyl-propionylamino)-3-(1H-indol-3-yl)-propionicacid methyl ester.

The crude product from 2A 1.55 g (7.1 mmol) was coupled to 1.44 g (7.1mmol) of N-t-BOC-α-methylalanine according to Procedure A to give an oilwhich was purified by silica gel chromatography using a gradient of 10%,20%, 30%, 40% and 50% ethyl acetate in hexane to elute. Recovered 1.32 gof(R)-2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-3-(1H-indol-3-yl)-propionicacid methyl ester.

C.(R)-2-(2-tert-Butoxycarbonylamino-2-methyl-propionylamino)-3-(1H-indol-3-yl)-propionicacid

To a solution of 1.03 g (2.64 mmol) of 2B in 10 mL of THF was added 381mg (9.1 mmol) of lithium hydroxide hydrate in 2 mL of water and themixture was stirred overnight at room temperature. Excess THF wasremoved by evaporation, and the basic aqueous mixture was extractedthree times with ethyl acetate, and then acidified to pH 4 with diluteacetic or hydrochloric acid. The product was extracted with ethylacetate and the combined organic extracts were washed with brine, driedover MgSO₄ and evaporated to give 1.03 g of 2C as an orange foam. MS(Cl, NH₃) 390 (MH⁺). ¹H NMR (CDCl₃ 300 MHz) δ 7.61 (d, 1H), 7.48 (d,1H), 7.27 (t, 1H), 7.10 (t, 1H), 4.81 (bs, 1H), 3.35 (m, 1H), 1.49 (s,6H), 1.32 (s, 9H).

D.{1-[2-[3a-(R,S)-(4-Fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

According to the method outlined in General Procedure A, 193 mg (0.51mmol) of 1D and 200 mg (0.51 mmol) of 2C were coupled and the residuewas purified by silica gel chromatography using an elution gradient of(1:1 v/v ethyl acetate:hexane) to 100% ethyl acetate to give 230 mg of2D. MS (Cl, NH₃) 633 (MH⁺).

E.2-Amino-N-[2-[3a-(R,S)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl]-1(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramidehydrochloride

To 230 mg (0.36 mmol) of 2D in 10 mL of ethanol was added 4 mL ofconcentrated HCl and the mixture was stirred at room temperature forabout 2 h. The mixture was concentrated and the residue was precipitatedfrom ethanol/hexane to give 130 mg of 2E as a white powder. MS (Cl, NH₃)533 (MH⁺). ¹HNMR (CD₃OD): (partial) δ 7.79 (d, 1 H), 7.48 (m, 1 H), 7.33(m, 2 H), 7.19-6.77 (m, 7 H), 6.54 (m, 1 H), 5.17 (m, 1 H), 4.02 (m, 1H), 3.11-2.68 (m, 6 H), 2.47 (m, 2 H), 2.03 (m, 2 H), 1.59 (m, 6 H).

EXAMPLE 32-Amino-N-[2-(3a-(R,S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1R-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramide

A. 4-Oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methylester

To a mixture of 7.00 g (36.2 mmol) of 4-oxo-piperidine-3-carboxylic acidmethyl ester and 8.82 g (72.3 mmol) of 4,4-dimethylaminopyridine in 200mL of methylene chloride at about 0° C. was added a solution of 7.88 g(36.2 mmol) of di-tert-butyldicarbonate in 150 mL of methylene chlorideover about 30 min. The mixture was warmed to room temperature and thenstirred for about 17 h. The mixture was concentrated and the residue wasdiluted with chloroform and washed three times each with 10% aqueousHCl, saturated aqueous sodium bicarbonate solution and brine, dried overMgSO₄ and concentrated to give 9.18 g of a clear yellow oil.

B. 3-(R,S)-Benzyl-4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butylester 3-methyl ester

To a solution of 500 g (19.4 mmol) 3A in 10 mL of DMF was added 745 mg(7.4 mmol) of sodium hydride (60% oil dispersion) and the mixture wasstirred at room temperature for about 15 min. A solution of 3.32 g (19.4mmol) benzylbromide in 15 mL of DMF was added to the stirring solutionby cannula and the mixture was stirred for about 42 h at roomtemperature. The mixture was diluted with ethyl acetate and washed oncewith water and four times with brine, dried over MgSO₄, and concentratedto give 6.0 g of 3B as a yellow oil. MS (Cl, NH₃) 348 (MH⁺).

C.3a-(R,S)-Benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]-pyridine-5-carboxylicacid tert-butyl ester

A mixture of 4.00 g (11.5 mmol) of 3B and 530 mg (11.5 mmol) ofmethylhydrazine in 100 mL of ethanol was heated at reflux for about 8 h.The mixture was concentrated and the residue was dissolved in 100 mLtoluene and heated at reflux for about 17 h. The mixture wasconcentrated and the residue was purified by silica gel chromatographyusing an elution gradient of (15:85 v/v ethyl acetate:hexane) to (75:25v/v ethyl acetate:hexane) to give 2.6 g of 3C as a clear colorless oil.MS (Cl, NH₃) 344 (MH⁺).

D.3a-(R,S)-Benzyl-2-methyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one

To 2.60 g (7.6 mmol) of 3C was added 20 mL of trifluoroacetic acid atabout 0° C. and the mixture was stirred for about 2.5 h. Ethyl acetatewas added and the solution was washed with 6N NaOH, dried over MgSO₄ andconcentrated to give 1.8 g of 3D. MS (Cl, NH₃) 244 (MH⁺).

E.{1-[2-(3a-(R,S)-Benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1R-(1H-indol-3-ylmethyl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

According to the method outlined in General Procedure A, 125 mg (4.6mmol) of 3C and 1.75 g (0.51 mmol) of 2C were coupled and the residuewas purified by silica gel chromatography using an elution gradient of(6:4 v/v ethyl acetate:hexane) to 7% methanol in ethyl acetate to give150 mg of 3E.

F.2-Amino-N-[2-(3a-(R,S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1R-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramidehydrochloride

To 150 mg (0.24 mmol) of 3E in 15 mL of ethanol was added 5 mL ofconcentrated HCl and the mixture was stirred at room temperature forabout 3 h. The mixture was concentrated and the residue was crystallizedfrom ethanol/hexane to give 100 mg of 3F. MS (Cl, NH₃) 515 (MH⁺). ¹HNMR(CD₃OD): δ 7.20-6.91 (m, 9 H), 6.56 (m, 1), 5.17 (m, 1 H), 4.05 (m, 1H), 2.96 (s, 3 H), 2.62 (m, 1 H), 2.38 (m, 1 H), 2.06 (m, 2 H), 1.61 (m,8 H).

EXAMPLE 42-Amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramidehydrochloride and2-Amino-N-[2-(3a-(S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramidehydrochloride

A.{1-[2-(3a-(R,S)-Benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

According to the method outlined in General Procedure A, 1.12 g (4.6mmol) of 3C and 1.75 g (0.51 mmol) of 1E were coupled to give a mixtureof diastereomers. The residue was purified by silica gel chromatographyusing an elution gradient of (1:1 v/v ethyl acetate:hexane) to 100%ethyl acetate to give 350 mg of less polar 4A isomer 1 and 250 mg ofmore polar 4A isomer 2. MS (Cl, NH₃) 606 (MH⁺) for both isomers.

B.2-Amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramidehydrochloride

To 250 mg (0.41 mmol) of 4A isomer 1 in 15 mL of ethanol was added 5 mLof concentrated HCl and the mixture was stirred at room temperature forabout 5 h. The mixture was concentrated and the residue was precipitatedfrom ethanol/hexane and dried under vacuum to give 130 mg of 4Bisomer 1. MS (Cl, NH₃) 506 (MH⁺). ¹HNMR (CD₃OD): δ 7.33 (m, 5 H), 7.14(m, 5 H), 5.22 (m, 1 H), 4.57 (m, 3 H), 3.80 (m, 2 H), 3.14 (m, 1 H),3.04 (s, 3 H), 2.96 (m, 2 H), 2.61 (m, 2 H), 1.63 (m, 7 H).

C.2-Amino-N-[2-(3a-(S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramidehydrochloride

To 250 mg (0.41 mmol) of 4A isomer 2 in 15 mL of ethanol was added 5 mLof concentrated HCl and the mixture was stirred at room temperature forabout 5 h. The mixture was concentrated and the residue was precipitatedfrom ethanol/hexane and dried under vacuum to give 120 mg of 4C isomer2. MS (Cl, NH₃) 506 (MH⁺). ¹HNMR (CD₃OD): δ 7.31 (m, 5 H), 7.13 (m, 5H), 6.78 (m, 1 H), 5.28 (m, 1 H), 4.62 (m, 3 H), 3.81 (M, 2 H), 3.14 (m,1 H), 2.62 (m, 3 H), 1.58 (m, 7 H).

D.2-Amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramidemethanesulfonate

Saturated aqueous sodium bicarbonate was added to 3.60 g (6.6 mmol) of4B isomer 1 and the mixture was extracted with ethyl acetate. Theorganic layer was dried over MgSO₄ and concentrated. The residue wasdissolved in ethyl acetate, cooled to about 0° C. and 0.43 mL (6.6 mmol)of methane-sulfonic acid was added and the mixture was stirred for about0.5 h. Hexane (200 mL) was added to the solution and the mixture wasstirred for about 1 h and filtered to give 3.40 of a white solid. Thesolid was recrystallized from 3% aqueous ethyl acetate to give 2.55 g of4D isomer 1 as a white crystalline solid. MS (Cl, NH₃) 506 (MH⁺).

EXAMPLE 52-Amino-N-[1-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-4-phenyl-(R)-butyl]-isobutyramidehydrochloride and2-Amino-N-[1-(3a-(S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-4-phenyl-(R)-butyl]-isobutyramidehydrochloride

A. 2-Oxo-5,6-diphenyl-3-(3-phenyl-allyl)-morpholine-4-carboxylic acidt-butyl ester

To an about −78° C. solution of 1.38 g (70.0 mmol) of cinnamyl bromideand 4.94 g (14.0 mmol) oft-butyl-(2S,3R)-(+)-6-oxo-2,3-diphenyl-4-morpholine carboxylate in 350mL of anhydrous THF was added 28 mL (28 mmol) of 1M sodiumbistrimethylsilylamide in THF. The mixture was stirred at about −78° C.for about 1.5 h and then poured into 750 mL of ethyl acetate. Themixture was washed twice with brine, dried over MgSO₄ and concentratedto give a yellow oil. The oil was stirred in 150 mL of hexane overnightand the precipitated solid was then collected by filtration to give 3.2g of 5A as a white solid.

B. 5(S),6(R)-Diphenyl-3(R)-(3-phenyl-allyl)-morpholin-2-one

To 2.97 g (6.33 mmol) of 5A was added 20 mL of trifluoroacetic acid atabout 0° C. and the mixture was stirred for about 2 h and thenconcentrated. The residue was dissolved in water and basified withaqueous NaOH until a pH of 10 was maintained. The mixture was extractedthree times with ethyl acetate and the combined organic extracts werewashed with brine, dried over MgSO₄ and concentrated to give an orangeoil which was purified by silica gel chromatography (10:90 v/v ethylacetate:hexane) to give 880 mg of 6B as a white solid.

C. 2-(R)-Amino-5-phenyl-pentanoic acid

A mixture of 440 mg (1.19 mmol) of 5B and 120 mg of palladium chloridein 20 mL of ethanol and 10 mL of THF was hydrogenated at 45 psi. forabout 16 h. The mixture was filtered through diatomaceous earth andconcentrated, and the residue was triturated with ether to give 240 mgof 5C as a white solid.

D. 2-tert-Butoxycarbonylamino-2-methyl-propionic acid2,5-dioxo-pyrrolidin-1-yl ester

To a slurry of 5.0 g (24.6 mmol) of N-t-BOC-α-methylalanine in 13.5 mLof methylene chloride was added 3.40 g (29.6 mmol) ofN-hydroxysuccinimide and 5.65 g (29.6 mmol) of EDC. The slurry wasstirred for about 17 h at room temperature. The mixture was diluted withethyl acetate and washed twice each with water, saturated sodiumbicarbonate solution and brine. Dried over MgSO₄ and concentrated. Theproduct was purified by silica gel chromatography (1:1 v/v ethylacetate:hexane) to give 5.2 g of the title compound of this part D as awhite solid.

E.(R)-2-(2-tert-Butoxycarbonylamino-2-methyl-propionylamino)-5-phenyl-pentanoicacid

A mixture of 203 mg (1.05 mmol) of 5D, 378 mg (1.26 mmol) of 5C and 434mg (3.36 mmol) of diisopropylethylamine in 2 mL of DMF was stirredover-night. The mixture was diluted with ethyl acetate and extractedtwice with 1N HCl. The aqueous phase was extracted once with ethylacetate. The pooled organic extracts were washed three times with waterand once with brine. The mixture was dried over MgSO₄ and concentrated.The residue was purified by silica gel chromatography using 80%chloroform in hexane followed by 100% chloroform followed by 10%methanol in chloroform to give 127 mg of 5E.

F.{1-[1-(3a-(R,S)-Benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-4-phenyl-(R)-butylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

According to the method outlined in General Procedure A, 130 mg (0.53mmol) of 3C and 200 mg (0.53 mmol) of 5E were coupled to give a mixtureof diastereomers. The residue was purified by silica gel chromatographyusing an elution gradient of (1:1 v/v ethyl acetate:hexane) to 100%ethyl acetate to give 40 mg of less polar 5F isomer 1 and 40 mg of morepolar 5F isomer 2. MS (Cl, NH₃) 604 (MH⁺) for both isomers.

G.2-Amino-N-[1-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-4-phenyl-(R)-butyl]-isobutyramidehydrochloride

To 40 mg (0.07 mmol) of 5F isomer 1 in 10 mL of ethanol was added 4 mLof concentrated HCl and the mixture was stirred at room temperature forabout 4 h. The mixture was concentrated and the residue was precipitatedfrom methylene chloride/hexane and dried under vacuum to give 30 mg of5G isomer 1. MS (Cl, NH₃) 504 (MH⁺). ¹HNMR (CD₃OD): (partial) δ 7.19 (m,10 H), 4.37 (m, 1 H), 3.02 (m, 6 H), 2.67 (m, 4 H), 1.83 (m, 4 H), 1.62(s, 6 H), 1.28 (m, 1 H).

H.2-Amino-N-[1-(3a-(S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-4-phenyl-(R)-butyl]-isobutyramidehydrochloride

To 40 mg (0.07 mmol) of 5F isomer 2 in 10 mL of ethanol was added 4 mLof concentrated HCl and the mixture was stirred at room temperature forabout 4 h. The mixture was concentrated and the residue was precipitatedfrom methylene chloride/hexane and dried under vacuum to give 30 mg of5H isomer 2. MS (Cl, NH₃) 504 (MH⁺). ¹HNMR (CD₃OD): (partial) 7.25 (m, 9H), 6.88 (m, 1 H), 3.04 (s, 3 H), 2.71 (m, 4 H), 2.48 (m, 2 H), 1.75 (m,4 H), 1.62 (m, 6 H), 1.28 (m, 1 H).

EXAMPLE 62-Amino-N-[2-(3a-(R,S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramidehydrochloride

A.{1-[2-(3a-(R,S)-Benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

According to the method outlined in General Procedure A, 200 mg (0.82mmol) of 3C and 320 mg (0.82 mmol) of 1E were coupled to give a mixtureof diastereomers. The residue was purified by silica gel chromatographyusing an elution gradient of (1:1 v/v ethyl acetate:hexane) to 10%methanol in ethyl acetate to give 170 mg of 6A.

B.2-Amino-N-[2-(3a-(R,S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramidehydrochloride

To 170 mg (0.28 mmol) of 6A in 20 mL of ethanol was added 5 mL ofconcentrated HCl and the mixture was stirred at room temperature forabout 2.5 h. The mixture was concentrated and the residue wasprecipitated from ethanol/hexane to give 70 mg of 6B. MS (Cl, NH₃) 506(MH⁺). ¹HNMR (CD₃OD): δ 7.32 (m, 5 H), 7.16 (m, 5 H), 5.22 (m, 1 H),4.67 (m, 1 H), 4.55 (m, 2 H), 3.79 (m, 2 H), 3.12 (m, 2 H), 3.00 (m, 6H), 2.71 (m, 3 H), 1.56 (m, 8 H).

EXAMPLE 72-Amino-N-[2-(3a-benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramidehydrochloride

A.3a-(R,S)-Benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

To 555 mg (1.60 mmol) of 3B in 27 mL of ethanol was added 240 mg (1.60mmol) of ethylhydrazineoxalate and the mixture was heated at reflux forabout 4 h. The mixture was concentrated and the residue was purified bysilica gel chromatography using an elution gradient of (10:1 v/vhexane:etyhyl acetate) to (3:7 v/v hexane:ethyl acetate) to give 357 mgof 7A. MS (Cl, NH₃) 358 (MH⁺).

B.3a-(R,S)-Benzyl-2-ethyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one

To 350 mg (0.98 mmol) of 7A in 3 mL of ethanol was added 1.5 mL ofconcentrated HCl and the mixture was stirred at room temperature forabout 2 h. The mixture was concentrated to give 257 mg of 7B. MS (Cl,NH₃) 258 (MH⁺).

C.{1-[2-(3a-(R,S)-Benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hyexahydro-pyrazolo[4,3-c]pyridin-5-yl-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl]-carbamicacid tert-butyl ester

According to the method outlined in General Procedure A, 82 mg (0.28mmol) of 7B and 100 mg (0.26 mmol) of 2C were coupled and the residuewas purified by silica gel chromatography using an elution gradient of100% methylene chloride to 2% methanol in methylene chloride to give 110mg of 7C. MS (Cl, NH₃) 629 (MH⁺).

D.2-Amino-N-[2-(3a)-(R,S)-benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramidehydrochloride

To 100 mg (0.15 mmol) of 7C in 2 mL of ethanol was added 1 mL ofconcentrated HCl and the mixture was stirred at room temperature forabout 2 h. The mixture was concentrated to give 72 mg of 7D as acolorless foam. MS (Cl, NH₃) 529 (MH⁺).

EXAMPLE 82-Amino-N-[2-(3a-(R)-benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl2-oxo-ethyl]-isobutyramidehydrochloride and2-Amino-N-[2-(3a-(S)-benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramidehydrochloride

A.{1-[2-(3a-Benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

According to the method outlined in General Procedure A, 85 mg (0.29mmol) of 7B and 100 mg (0.26 mmol) of 1E were coupled to give a mixtureof diastereomers. The residue was purified by silica gel chromatographyusing an elution gradient of 100% methylene chloride to 2% methanol inmethylene chloride to give 6 mg of less polar 8A isomer 1 and 11 mg ofmore polar 8A isomer 2. MS (Cl, NH₃) 620 (MH⁺) for both isomers.

B.2-Amino-N-[2-(3a-(R)-benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramidehydrochloride

To 5.7 mg (0.009 mmol) of 8A isomer 1 in 1 mL of ethanol was added 0.4mL of concentrated HCl and the mixture was stirred at room temperaturefor about 3 h. The mixture was concentrated to give 4.7 mg of 8Bisomer 1. MS (Cl, NH₃) 520 (MH⁺). ¹HNMR (CD₃OD): (partial)δ7.41-7.05 (m,10 H), 5.20 (m, 1 H), 4.61 (m, 1 H), 4.52 (s, 2 H), 3.71 (m, 1 H), 3.60(m, 1 H), 2.61 (m, 3 H), 1.39 (m, 9 H).

C.2-Amino-N-[2-(3a-(S)-benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramidehydrochloride

To 10 mg (0.016 mmol) of 8A isomer 2 in 1 mL of ethanol was added 0.4 mLof concentrated HCl and the mixture was stirred at room temperature forabout 3 h. The mixture was concentrated to give 8 mg of 8C isomer 2. MS(Cl, NH₃) 520 (MH⁺). ¹HNMR (CD₃OD): (partial)δ7.43-7.00 (m, 10 H), 6.81(m, 1 H), 5.32 (m, 1 H), 4.63 (m, 2 H), 4.53 (m, 1 H), 1.37 (m, 9 H).

EXAMPLE 92-Amino-N-[2-(2-benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramidehydrochloride

A.2-Benzyl-3-hydroxy-2,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

A mixture of 800 mg (3.11 mmol) of 3B and 495 mg (3.11 mmol) ofbenzylhydrazine dihydrochloride and 423 mg (3.11 mmol) of sodium acetatetrihydrate in 15 mL of ethanol was heated at reflux for about 17 h. Themixture was concentrated and the residue was dissolved in 100 mL oftoluene and heated at reflux for about 48 h. The mixture was dilutedwith ethyl acetate and washed with brine, dried over MgSO₄ andconcentrated and the residue was purified by silica gel chromatographyusing 100% ethyl acetate followed by 5% methanol in methylene chlorideto give 530 mg of 9A as a light brown solid. MS (Cl, NH₃) 330 (MH⁺).

B. 2-Benzyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-ol

To 411 mg (1.24 mmol) of 3E in 30 mL of ethanol was added 10 mL ofconcentrated HCl and the mixture was stirred at room temperature forabout 30 min. The mixture was concentrated and the residue wascrystallized from methanol/ethyl acetate to give 353 mg of 9B. MS (Cl,NH₃) 230 (MH⁺).

C.{1-[2-(2-Benzyl-3-hydroxy-2,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-R-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

According to the method outlined in General Procedure A, 100 mg (0.38mmol) of 9B and 145 mg (0.38 mmol) of 1E were coupled and the reside waspurified by silica gel chromatography (95:5 v/v methanol:methylenechloride) to give 42 mg of 9C as a white solid. MS (Cl, NH₃) 592 (MH⁺).

D.2-Amino-N-[2-(2-benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramidehydrochloride

To 42 mg (0.07 mmol) of 9D in 20 mL of ethanol was added 6 mL ofconcentrated HCl and the mixture was stirred at room temperature forabout 30 min. The mixture was diluted with ethanol concentrated and theresidue was precipitated from methanol/ethyl acetate to give 35 mg of 9Das a white solid. MS (Cl, NH₃) 492 (MH⁺). ¹HNMR (CD₃OD): (partial)7.41-7.16 (m, 10 H), 5.19 (m, 3 H), 4.48 (m, 4 H), 3.88 (m, 1 H), 3.74(m, 2 H), 2.68 (m, 6 H).

EXAMPLE 102-Amino-N-{2-[3a-(R)-benzyl-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5yl]-1-(R)-benzyloxymethyl-2-oxo-ethyl}-isobutyramidehydrochloride and2-Amino-N-{2-[3a-(S)-benzyl-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5yl]-1-(R)-benzyloxymethyl-2-oxo-ethyl}-isobutyramide hydrochloride

A.3a-(R,S)-Benzyl-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,3a4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

A mixture of 840 mg (2.42 mmol) of 3B and 276 mg (2.42 mmol) of2,2,2-trifluoroethylhydrazine (70% in water) in 20 mL of ethanol washeated at reflux for about 5 h and then concentrated. The residue wasdissolved in 40 mL of toluene and heated at reflux for about 17 h. Themixture was concentrated and the residue was purified by silica gelchromatography (9:1 v/v hexane:ethyl acetate) to give 703 mg of 10A as ayellow oil. MS (Cl, NH₃) 412 (MH⁺).

B.3a-(R,S)-Benzyl-2-(2,2,2-trifluoro-ethyl)-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one

To 600 mg (1.46 mmol) of 10A at about 0° C. was added 3 mL of coldtrifluoroacetic acid and the mixture was stirred for about 3 h, allowingthe solution to reach room temperature as it did so. The mixture wasconcentrated and the residue was dissolved in water and the solution wasbasified to pH 11 with 5N NaOH and then saturated with potassiumcarbonate. The solution was extracted three times with ethyl acetate andthe combined organic extracts were washed with brine, dried over MgSO₄and concentrated to give 345 mg of 10B as an opaque oil. MS (Cl, NH₃)312 (MH⁺).

C.{1-(2-[3a-(R,S)-Benzyl-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-1-(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl}-1-methyl-ethyl)-carbamicacid tert-butyl ester

According to the method outlined in General Procedure A, 137 mg (0.44mmol) of 10B and 167 mg (0.44 mmol) of 1E were coupled to give a mixtureof diastereomers. The residue was purified by silica gel chromatographyusing an elution gradient 100% methylene chloride to 5% methanol inmethylene chloride to give 128 mg of less polar 10 C isomer 1 and 63 mgof more polar 10C isomer 2. MS (Cl, NH₃) 674 (MH⁺) for both isomers.

D.2-Amino-N-{2-[3a-(R)-benzyl-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5yl]-1-(R)-benzyloxymethyl-2-oxo-ethyl}-isobutyramidehydrochloride

To 120 mg (0.18 mmol) of 10C isomer 1 in 3.5 mL of ethanol was added 1.5mL of concentrated HCl and the mixture was stirred at room temperaturefor about 2 h. The mixture was concentrated to give 94 mg of 10D isomer1 as an off-white powder. MS (Cl, NH₃) 574 (MH^(+).) ¹HNMR (CD₃OD):(partial) δ7.31 (m, 5H), 7.18 (m, 5 H), 5.21 (m, 1 H), 4.57 (m, 3 H),4.26 (m, 1H), 4.08 (m, 1 H), 3.79 (m, 2 H), 3.09 (m, 4 H), 2.65 (m, 2H), 1.63 (m, 6 H).

E.2-Amino-N-{2-[3a-(S)-benzyl-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-1-(R)-benzyloxymethyl-2-oxo-ethyl}-isobutyramidehydrochloride

To 53 mg (0.079 mmol) of 10 C isomer 2 in 3.5 mL of ethanol was added1.5 mL of concentrated HCl and the mixture was stirred at roomtemperature for about 2 h. The mixture was concentrated to give 41 mg of10E i somer 2 as a light yellow solid. MS (Cl, NH₃) 574 (MH⁺). ¹HNMR(CD₃OD): (partial) δ7.33 (m, 5 H), 7.15 (m, 4 H), 6.81 (m, 1H), 5.30 (m,1 H), 4.67 (m, 4 H), 4.15 (m, 2 H), 3.77 (m, 2 H), 3.09 (m, 3 H), 2.64(m, 3 H), 1.58 (m, 6 H).

EXAMPLE 112-Amino-N-[2-(3a-(R)-benzyl-2-tert-butyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramidemethanesulfonate and2-Amino-N-[2-(3a-(S)-benzyl-2-tert-butyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramidemethanesulfonate

A. 3a-(R,S)-Benzyl-2-tert-butyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butylester

To 2.07 g (5.95 mmol) of 14B in 40 mL of ethanol was added 0.97 g (7.7mmol) of tert-butylhydrazine hydrochloride and 0.63 g (7.7 mmol) ofsodium acetate and the mixture was heated at about 70° C. for about 17h. The mixture was cooled and the solution decanted from the precipitateand concentrated. The residue was dissolved in 80 mL of toluene andheated at reflux for about 6 h. The mixture was concentrated and theresidue was purified by silica gel chromatography (9:1 v/v hexane:ethylacetate) to give 1.7 g of 11A. MS (Cl, NH₃) 386 (MH⁺).

B.3a-(R,S)-Benzyl-2-tert-butyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one

To 535 mg (1.39 mmol) of 11A in 20 mL of methylene chloride was added225 μL of methanesulfonic acid and the mixture was stirred for about 1.5h at room temperature. The mixture was diluted with ethyl acetate andwashed twice with 1 N NaOH and once with brine, dried over Na₂SO₄ andconcentrated to give 246 mg of 11B. MS (Cl, NH₃) 286 (MH⁺).

C.{1-[2-(3a-(R,S)-Benzyl-2-tert-butyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

According to the method outlined in General Procedure A, 246 mg (0.86mmol) of 11B and 328 mg of 14F were coupled to give a mixture ofdiastereomers.The residue was purified by silica gel chromatography (6:4v/v hexane/ethyl acetate) to give 250 mg of less polar 11C isomer 1 and90 mg more polar 11C isomer 2. MS (Cl, NH₃) 648 (MH⁺) for both isomers.

D.2-Amino-N-[2-(3a-(R)-benzyl-2-tert-butyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramidemethanesulfonate

To 210 mg (0.32 mmol) of 11C isomer 1 in 15 mL of methylene chloride atabout 0° C. was added 28 μL (0.44 mmol) of methanesulfonic acid. The icebath was removed and the mixture was stirred for about 3 h, diluted with15 mL of diethyl ether and the precipitated solid was collected byfiltration to give 100 mg of 11D isomer 1. MS (Cl, NH₃) 548 (MN⁺). ¹HNMR (CD₃OD): (partial) δ7.33 (m, 5 H), 7.27-7.07 (m, 5 H), 5.21 (m, 1H), 4.54 (m, 3 H), 3.86 (m, 3 H), 3.10 (m, 4 H), 2.61 (s, 3 H), 1.62 (m,6 H), 1.18 (s, 9 H).

E.2-Amino-N-[2-(3a-(S)-benzyl-2-tert-butyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramidemethanesulfonate

To 85 mg (0.13 mmol) of 11C isomer 2 in 10 mL of methylene chloride atabout 0° C. was added 21 μL (0.32 mmol) of methanesulfonic acid. The icebath was removed and he mixture was stirred for about 3 h, diluted with20 mL of diethyl ether and the precipitated solid was collected byfiltration to give 46 mg of 11E isomer 2. MS (Cl, NH₃) 548 (MH⁺). ¹H NMR(CD₃OD): (partial) δ8.28 (br d, 1 H), 7.32 (m, 5 H), 7.18 (m, 4 H), 6.84(m, 1 H), 5.31 (m, 1 H), 4.60 (m, 3 H), 3.70 (m, 3 H), 3.18-2.92 (m, 3H), 2.68 (s, 3 H), 1.57 (m, 6 H), 1.13 (s, 9 H).

EXAMPLE 122-Amino-N-[1-(R)-(1H-indol-3-ylmethyl)-2-(2-methyl-3-oxo-3a-(R,S)-pyridin-2-yimethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-isobutyramidedihydrochloride

A. 4-Oxo-3-(R,S)-pyridin-2-ylmethyl-piperdine-1,3-dicarboxylic acid1-tert-butyl ester 3-methyl ester

To a solution of 2.00 g (7.8 mmol) of 3A in 32 mL of THF was added 468mg (11.7 mmol) of sodium hydride (60% oil dispersion) at about 0° C. andthe mixture was stirred for about 30 min. A solution of 762 mg (6.0mmol) 2-picolyl chloride in 5 mL of THF was added to the stirringsolution over about 5 min, followed by the addition of 432 mg (2.6 mmol)of potassium iodide. The ice bath was removed and the mixture was heatedfor about 17 h at reflux. The mixture was diluted with ethyl acetate andwashed once with water and once with brine, dried over MgSO₄, andconcentrated. The residue was purified by silica gel chromatographyusing (6:4 v/v ether:hexane) followed by (6:4 v/v ethyl acetate:hexane)to give 1.2 g of 12A. MS (Cl, NH₃) 349 (MH⁺).

B.2-Methyl-3-oxo-3a-(R,S)-pyridin-2-ylmethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

A mixture of 1.20 g (3.45 mmol) of 12A and 159 mg (3.45 mmol) ofmethylhydrazine in 20 mL of ethanol was heated at reflux for about 6.5h. The mixture was concentrated and the residue was dissolved in 25 mLtoluene and heated at reflux for about 17 h. The mixture wasconcentrated and the residue was purified by silica gel chromatography(65:35 v/v ethyl acetate:hexane) to give 450 mg of 12B. MS (Cl, NH₃) 345(MH⁺).

C.2-Methyl-3a-(R,S)-pyridin-2-ylmethyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-onedihydrochloride

A mixture of 450 mg (1.30 mmol) of 12B in 2 mL of 4M HCl/dioxane wasstirred at room temperature for about 4.5 h. The mixture wasconcentrated to give 450 mg of 12 C. MS (Cl, NH₃) 245 (MH⁺).

D.{1-[1-(1-(R)-H-indol-3-ylmethyl)2-(2-methyl-3-oxo-3a-(R,S)-pyridin-2-yimethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

According to General Procedure A, 108 mg (0.31 mmol) of 12C and 122 mg(0.31 mmol) of 2C were coupled and the residue was purified by silicagel chromatography 95:5 v/v ethyl acetate:methanol) to give 118 mg of12D. MS (Cl, NH₃) 616 (MH⁺).

E.2-Amino-N-[1-(R)-(1H-indol-3-ylmethyl)-2-(2-methyl-3-oxo-3a-(R,S)-pyridin-2-ylmethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-isobutyramidedihydrochloride

A mixture of 110 mg (0.18 mmol) of 12D in 1 mL of 4M HCl/dioxane wasstirred at room temperature for 17 h. The mixture was concentrated togive 51 mg of 12E. MS (Cl, NH₃) 516 (MH₃₀ ). ¹HNMR (CD₃OD): (partial)δ8.91-8.52 (m, 2 H), 8.04 (m, 2 H), 7.76-7.50 (m, 3 H), 6.82 (m, 1 H),4.62 (m, 1 H), 3.36 (s, 3 H), 1.63 (s, 6 H).

EXAMPLE 132-Amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-3-oxo-3a-(R,S)-pyridin-2ylmethyl:2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl-]-isobutyramidedihydrochloride

A.{1-[1-(R)-Benzyloxymethyl-2-(2-methyl-3-oxo-3a-(R,S)-pyridin-2-ylmethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

According to General Procedure A, 86 mg (0.27 mmol) of 12C and 103 mg(0.37 mmol) of 1E were coupled and the residue was purified by silicagel chromatography (95:5 v/v ethyl acetate:hexane) to give 82 mg of 13A.

B.2-Amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-3-oxo-3a-(R,S)-pyridin-2-ylmethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-isobutyramidedihydrochloride

A mixture of 75 mg (0.12 mmol) of 13A in 1 mL of 4M HCl/dioxane wasstirred at room temperature for about 17 h. The mixture was concentratedto give 80 mg of 13B. MS (Cl, NH₃) 507 (MH⁺). ¹ HNMR (CD₃OD): (partial)δ8.78 (m, 1 H), 8.46 (m, 1H), 8.13-7.82 (m, 2 H), 7.32 (m, 5 H), 4.57(m, 3H), 3.96 (m, 1 H), 3.82 (m, 2H), 1.63 (m, 6 H).

EXAMPLE 142-Amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide.

A. 4-Oxo-piperdine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methylester

To a mixture of 100.0 g (516.4 mmol) of 4-oxo-piperdine-3-carboxylicacid methyl ester and 63 g (516.4 mmol) of 4,4-dimethylaminopyridine in1 L of methylene chloride at about 0° C. was added a solution of 113.0 g(516.4 mmol) of di-tert-butyldicarbonate in 100 mL of methylene chlorideover about 90 min. The mixture was slowly warmed to room temperature andthen stirred for about 19 h. The mixture was washed three times eachwith 10% aqueous HCl, saturated aqueous sodium bicarbonate solution andbrine, dried over MgSO₄ and concentrated to give 130.5 g of 14A as anamorphous solid. ¹HNMR (CDCl₃ ): δ4.03 (br, 2 H); 3.74 (s, 3 H), 3.56(t, 2 H), 2.36 (t, 2 H), 1.42 (s, 9 H).

B. 3-(R)-Benzyl-4-oxo-piperdine-1,3-dicarboxylic acid 1-tert-butyl ester3-methyl ester

To a stirred suspension of 11.7 g (293 mmol) of sodium hydride (60% oildispersion washed twice with 100 mL of hexane) in 100 mL of DMF wasadded a solution of 65.4 g (254 mmol) of 14A in 150 mL of DMF at about0° C. over about 45 min. The ice bath was removed and the mixture wasstirred at room temperature for about 45 min. The mixture was recooledto about 0° C. and 35.2 mL (296 mmol) of benzylbromide in 200 mL of DMFwas added dropwise to the stirring solution and the mixture was stirredfor about 23 h at room temperature. To the solution was carefully added550 mL of water and the mixture was stirred for about 30 min. Themixture was extracted three times with ethyl acetate and the combinedorganic extract were washed five times with water, once with brine,dried over MgSO₄ and concentrated to give 98 g of a yellow oil. The oilwas crystallized from hexane to give 71 g of 14B as a white solid. MS(Cl, NH₃) 348 (MH⁺). ¹HNMR (CDCl₃): (partial) δ7.23 (m, 3 H), 7.13 (m, 2H), 4.58 (br m, 1 H), 4.18 (br, 1 H), 3.63 (s, 3 H), 3.28-2.96 (m, 4 H),2.72 (m, 1 H), 2.43 (m, 1 H), 1.44 (s, 9 H).

C.3a)-(R)-Benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

A mixture of 47.0 g (135 mmol) of 14B, 38.9 g (270 mmol) ofmethylhydrazine sulfate and 44.3 g (540 mmol) of sodium acetate in 900mL of ethanol was heated at reflux for about 17 h under nitrogen. Themixture was concentrated and the residue was dissolved in ethyl acetateand washed three times with water and once with brine, dried over MgSO₄and concentrated to give a yellow oil. The oil was stirred in 750 mL ofhexane for about 3 h to give 41.17 g of 14C as a white solid. MS (Cl,NH₃) 344 (MH⁺). ¹HNMR (CDCl₃): (partial)δ7.19 (m, 3 H), 7.05 (m, 2 H),4.61 (br m, 2 H), 3.24 (m, 1 H), 3.09 (s, 3 H), 3.01 (m, 1 H), 2.62 (m,4 H), 1.52 (s, 9 H).

D.3a)-(R,S)-Benzyl-2-methyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-onehydrochloride

Anhydrous HCl was bubbled through a solution of 24.55 g (71.5 mmol) of14C in 800 mL of diethyl ether at about 0° C. for about 12 min. Themixture was stirred for about 3 h, during which time a white precipitateformed. The precipitated solid was collected by filtration and to give19.2 g of 14D. MS (Cl, NH₃) 244 (MH₊). ¹HNMR (CD₃OD): (partial) δ7.25(m, 3 H), 7.05 (m, 2 H), 3.77 (m, 2 H), 3.51 (d, 1 H), 3.25 (m, 1 H),3.17 (m, 3 H), 3.03 (s, 3 H), 2.81 (m, 1 H).

E. 2-tert-Butoxycarbonylamino-2-methyl-propionic acid2,5-dioxo-pyrrolidin-1-yl ester

To a stirring solution of 100.0 g (492 mmol) of Boc-α-methylalanine and94.0 g (492 mmol) of EDC in 2 L of methylene chloride at about 0° C. wasadded 56.63 g (492 mmol) of N-hydroxysuccinimide in portions and thereaction was then allowed to warm to room temperature. The mixture wasstirred for about 24 h and washed twice each with saturated aqueoussodium bicarbonate solution and brine, dried over Na₂SO₄ andconcentrated to give 124.0 g of 14E as a white solid. ¹HNMR (CDCl₃):δ4.96 (br, 1 H), 2.82 (s, 4 H), 1.66 (s, 6 H), 1.48 (s, 9 H).

F.3-(R)-Benzyloxy-2-(2-tert-butoxycarbonylamino-2-methyl-proplonylamino)-propionicacid

A mixture of 50.5 g (168 mmol) of 14E, 33.5 g (168 mmol) ofo-benzyl-D-Serine and 51.05 g (505 mmol) of triethylamine in 400 mL ofdioxane and 100 mL of water was heated at about 45° C. for about 16 h.The mixture was diluted with ethyl acetate and acidified to pH 2 withacetic acid. The layers were separated and the organic phase was washedwith brine, dried over Na₂SO₄ and concentrated to give 650 g of 14F as awhite solid. ¹HNMR (CD₃OD): (partial) δ7.55 (d, 1 H), 7.29 (m, 5 H),4.52 (m, 1 H), 4.48 (s, 2 H), 3.84 (d of d, 1 H), 3.69 (d of d, 1 H),1.42 (s, 6 H), 1.38 (s, 9 H).

G.3a-(R)-Benzyl-2-methyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-oneL-tartrate

To a mixture of 5.00 g (20.6 mmol) of the free base of 14D and 3.09 g(20.6 mmol) of L-tartaric acid in 80 mL of acetone and 3.2 mL of waterwas heated under nitrogen at about 70° C. for about 70 h, during whichtime the reaction mixture became a thick suspension and an additional 20mL of acetone was added. The reaction mixture was cooled slowly to roomtemperature and then filtered. The solid that was collected was washedwith acetone and dried under vacuum to give 7.03 g of 14G as a whitesolid.

H.3a-(R)-Benzyl-2-methyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one

To a suspension of 5.00 g (12.7 mmol) of 14G in 80 mL of methylenechloride at about 0° C was added 1.72 mL (25.4 mmol) of ammoniumhydroxide and the mixture was stirred for about 15 min. The coldsolution was filtered and used immediately in the next step.

{1-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5yl)-1-(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester.

A mixture of 4.83 g (12.7 mmol) of 14 F, the solution from 14H, 2.60 g(19.1 mmol) of HOAT, and 2.45 g (12.8 mmol) of EDC was stirred at about0° C. under nitrogen for about 1 h and then warmed to room temperatureand stirred for about 16 h. The mixture was filtered and the filtratewas washed with saturated aqueous sodium bicarbonate and water, driedover MgSO₄ and concentrated to give 7.35 g of 14I as a white solid.

2-Amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]isobutyramide.

To 755 mg (1.25 mmol) of 14I in 7 mL of methylene chloride at about 0°C. was added 3.5 mL of cold trifluoroacetic acid and the mixture wasstirred for about 1 h at about 0° C. The mixture was allowed to warm toroom temperature and stirred for about 2 h. The mixture was concentratedand co-evaporated twice with toluene. The residue was dissolved inchloroform and washed twice with saturated aqueous sodium bicarbonateand once each with water and brine. The mixture was dried over MgSO₄ andconcentrated to give 594 mg of 14J as an oil.

EXAMPLE 152-Amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-isobutyramidehydrochloride

A.2-Methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

A mixture of 3.00 g (11.66 mmol) of 3A and 537 mg (11.66 mmol) ofmethylhydrazine in 100 mL of ethanol was heated at reflux for about 17h. The mixture was concentrated and the residue was dissolved in 100 mLtoluene and heated at reflux for about 17 h. The mixture was dilutedwith ethyl acetate, and washed twice with brine, dried over MgSO₄ andconcentrated. The residue was purified by silica gel chromatographyusing an elution gradient of 100% ethyl acetate to 5% methanol inmethylene chloride to give 2.28 g of 15A as a white solid. ¹HNMR(CD₃OD): δ 4.20 (s, 2H), 3.67 (t, 2H), 3.43 (s, 3H), 2.58 (t, 2H), 1.48(s, 9H).

B. 2-Methyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-onehydrochloride

To 510 mg (2.01 mmol) of 15A in 30 mL of ethanol was added 10 mL ofconcentrated HCl and the mixture was stirred at room temperature forabout 35 min. The mixture was concentrated and the residue wascrystallized from methanol/ethyl acetate to give 425 mg of 15B as ayellow solid. ¹HNMR (CD₃OD): δ 4.27 (S, 2H), 3.71 (S, 3H), 3.56 (T, 2H),3.05 (T, 2H).

C.{1-[1-(R)-Benzyloxymethyl-2-(2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

According to the method outlined in General Procedure A, 100 mg (0.53mmol) of 15B and 202 mg (0.53 mmol) of 1E were coupled and the residuewas purified by silica gel chromatography (95:5 v/v methylenechloride:methanol) to give 54 mg of 15C as a white solid. MS (Cl, NH₃)516 (MH⁺).

D.2-Amino-N-[1-R-benzyloxymethyl-2-(2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-isobutyramidehydrochloride

To 54 mg (0.10 mmol) of 15C in 30 mL of ethanol was added 10 mL ofconcentrated HCl and the mixture was stirred at room temperature forabout 40 min. The mixture was concentrated and the residue wasprecipitated from methanol/ethyl acetate to give 50 mg of 15D. MS (Cl,NH₃) 416 (MH⁺). ¹HNMR (CD₃OD): (partial) δ 7.28 (m, 5H), 5.18 (m, 1H),4.69-4.38 (m, 4H), 3.88 (m, 1H), 3.73 (m, 2H), 3.68 (s, 2H), 3.61 (m,1H), 2.67 (m, 1H), 1.57 (s, 6H).

EXAMPLE 162-Amino-N-[2-(2-benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramidehydrochloride

A.2-Benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

A mixture of 800 mg (3.11 mmol) of 3A and 495 mg (3.11 mmol) ofbenzyl-hydrazine dihydrochloride in 15 mL of ethanol was heated atreflux for about 17 h. The mixture was concentrated and the residue wasdissolved in 100 mL toluene and heated at reflux for about 48 h. Themixture was diluted with ethyl acetate, and washed twice with brine,dried over Na₂SO₄ and concentrated. The residue was purified by silicagel chromatography using an elution gradient of 100% ethyl acetate to 5%methanol in methylene chloride to give 530 mg of 16A as a tan solid. MS(Cl, NH₃) 330 (MH⁺).

B. 2-Benzyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-onehydrochloride

To 411 mg (1.24 mmol) of 16A in 30 mL of ethanol was added 10 mL ofconcentrated HCl and the mixture was stirred at room temperature forabout 30 min. The mixture was concentrated and the residue wascrystallized from methanol/ethyl acetate to give 353 mg of 16B as ayellow solid. MS (Cl, NH₃) 230 (MH⁺). ¹HNMR (CD₃OD): δ 7.26-7.40 (m,5H), 5.22 (s, 2H), 4.12 (s, 2H), 3.53 (t, 2H), 3.00 (t, 2H).

C.(R)-2-(2-tert-Butoxycarbonylamino-2-methyl-propionylamino)-3-(1H-indol-3-yl)-propionicacid

To a stirring solution of 30.6 g (0.15 mol) of D-tryptophan, 30.4 g(0.30 mol) of N-methylmorpholine in 450 mL of (4:1) dioxane:water, wasadded 45.0 g (0.15 mol) of 14E and the mixture was stirred for about 72h. Excess dioxane was removed by evaporation and water and ethyl acetatewere added to the mixture. The pH of the solution was adjusted to 3 withconcentrated HCl and the layers were separated. The organic layer waswashed with water and brine, dried over MgSO₄ and concentrated. Theresidue was crystallized from ethyl acetate/hexanes to give 37.0 g of anoff-white solid.

D.{1-[2-(2-Benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

According to the method outlined in General Procedure A, 100 mg (0.38mmol) of 16B and 202 mg (0.53 mmol) of 16C were coupled and the residuewas purified by silica gel chromatography (95:5 v/v methylenechloride:methanol) to give 45 mg of 16D as a white solid. MS (Cl, NH₃)601 (MH⁺).

E.2-Amino-N-[2-(2-benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazole[4,3-c]pyridin-5-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramidehydrochloride

To 45 mg (0.07 mmol) of 16D in 60 mL of ethanol was added 20 mL ofconcentrated HCl and the mixture was stirred at room temperature for 35min. The mixture was concentrated and the residue was precipitated frommethanol/ethyl acetate to give 30 mg of 16E. ¹HNMR (CD₃OD): (partial) δ7.40 (m, 4H), 7.25 (m, 3H), 7.11 (m, 2H), 6.96 (m, 2H), 6.81 (m, 1H),5.38-4.93 (m, 3H), 4.46 (m, 1H), 4.22 (m, 1H), 3.96 (m, 1H), 3.69 (m,1H), 3.18 (m, 1H), 2.28 (m, 1H), 1.57 (m, 6H), 1.38 (m, 1H).

EXAMPLE 172-Amino-N-[1-benzyloxymethyl-2-(2,3a-dimethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-isobutyramidehydrochloride

A. 3-Methyl-4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester3-(R,S)-methyl ester

To a solution of 2.00 g (7.77 mmol) 3A in 30 mL of DMF was added 308 mg(7.77 mmol) of sodium hydride (60% oil dispersion) and the mixture wasstirred at room temperature for about 25 min. To the stirring solutionwas added 0.50 mL (7.77 mmol) of methyl iodide and the mixture wasstirred for about 17 h at room temperature. The mixture was diluted withethyl acetate and washed once with water and four times with brine,dried over MgSO₄, and concentrated. The residue was purified by silicagel chromatography (7:3 v/v hexane:ethyl acetate) to give 1.75 g of 17Aas a clear oil. MS (Cl, NH₃) 272 (MH⁺).

B.2,3a-(R,S)-Dimethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

A mixture of 1.62 g (9.50 mmol) of 17A and 435 mg (9.50 mmol) ofmethylhydrazine in 30 mL of ethanol was heated at reflux for about 4 h.The mixture was concentrated and the residue was dissolved in 50 mLtoluene and heated at reflux for about 14 h. The mixture was dilutedwith ethyl acetate, and washed twice with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatography (7:3v/v hexane:ethyl acetate) to give 1.00 g of 17B as a white solid. MS(Cl, NH₃) 268 (MH⁺).

C.2,3a-(R,S)-Dimethyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-onehydrochloride

To 1.00 g (3.74 mmol) of 17B in 40 mL of ethanol was added 8 mL ofconcentrated HCl and the mixture was stirred at room temperature forabout 35 min. The mixture was concentrated and the residue wascrystallized from methanol/ethyl acetate to give 850 mg of 17C as awhite solid. MS (Cl, NH₃) 168 (MH⁺).

D.{1-[1-(R)-Benzyloxymethyl-2-(2,3a-(R,S)-dimethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

According to the method outlined in General Procedure A, 150 mg (0.74mmol) of 17C and 514 mg (1.35 mmol) of 1E were coupled and the residuewas purified by silica gel chromatography (85:15 v/v hexane:ethylacetate) to give 185 mg of 17D as a white solid.

E.2-Amino-N-[1-benzyloxymethyl-2-(2,3a-(R,S)-dimethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-isobutyramidehydrochloride

To 173 mg (0.33 mmol) of 17B in 40 mL of ethanol was added 15 mL ofconcentrated HCl and the mixture was stirred at room temperature forabout 1 h. The mixture was concentrated and the residue was diluted withchloroform and washed with saturated aqueous sodium bicarbonate andbrine, dried over Na₂SO₄ and the residue was purified by silica gelchromatography using an elution gradient of 100% ethyl acetate to 10%diethylamine in ethyl acetate. The residue was dissolved in ethanol andacidified with aqueous HCl. The mixture was concentrated and the residuewas crystallized from methanol/ethyl acetate to give 65 mg of 17E as awhite solid. MS (Cl, NH₃) 502 (MH⁺). ¹HNMR (CD₃OD): (partial) δ 7.32 (m,5H), 5.14 (m, 1H), 4.53 (m, 3H), 3.71 (m, 3H), 2.97 (m, 1H), 2.83 (m,1H), 2.57 (m, 1H), 1.98 (m, 2H), 1.61 (m, 6H), 1.38 (s, 3H).

EXAMPLE 182-Amino-N-[2-(3a-(R)-benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramidehydrochloride and2-Amino-N-[2-(3a-(S)-benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramidehydrochloride

A. 3-Benzyl-4-oxo-piperidine-3-carboxylic acid methyl ester

To 200 mg (0.58 mmol) of 3B at about 0° C. was added 5 mL of coldtrifluoroacetic acid and the mixture was stirred for about 1 h. Themixture was concentrated and the residue was co-evaporated with ethylacetate and hexane. To the residue was added 2N NaOH to make it basicand the mixture was extracted with chloroform. The combined organicextracts were dried over MgSO₄ and concentrated to give 18A inquantitative yield.

B.3-(R,S)-Benzyl-1-[3-benzyloxy-2-(R)-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-propionyl]-4-oxo-piperidine-3-carboxylicacid methyl ester

According to the method outlined in General Procedure A, 1.77 g, (7.16mmol) of 18A and 3.04 g (8.0 mmol) of 14F were coupled to give a mixtureof diastereomers. The residue was purified by silica gel chromatography(7:3 v/v hexane:ethyl acetate) to give 820 mg of less polar 18B isomer 1and 1.14 g more polar 18B isomer 2. MS (Cl, NH₃) 611 (MH⁺) for bothisomers.

C.{1-[2-(3a-(R,S)-Benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

To a solution of 820 mg (1.32 mmol) of 18B isomer 1 in 13 mL of ethanolwas added 342 mg (2.63 mmol) of hydrazine sulfate and 431 mg (5.26 mmol)of sodium acetate and the mixture was heated at reflux for about 17 h.The mixture was concentrated and the residue was diluted with ethylacetate and washed with saturated aqueous sodium bicarbonate and brine,dried over MgSO₄ and concentrated. The residue was purified by silicagel chromatography using an elution gradient of 75% ethyl acetate inhexane to 100% ethyl acetate to give 550 mg of 18C isomer 1.

To a solution of 1.14 g (1.86 mmol) of 18B isomer 2 in 20 mL of ethanolwas added 485 mg (3.73 mmol) of hydrazine sulfate and 613 mg (7.48 mmol)of sodium acetate and the mixture was heated at reflux for about 17 h.The mixture was concentrated and the residue was diluted with ethylacetate and washed with saturated aqueous sodium bicarbonate and brine,dried over MgSO₄ and concentrated. The residue was purified by silicagel chromatography (75:25 v/v ethyl acetate/hexane) to give 710 mg of18C isomer 2.

D.2-Amino-N-[2-(3a-(R)-benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramidehydrochloride

To 200 mg (0.34 mmol) of 18C isomer 1 in 12 mL of ethanol was added 6 mLof concentrated HCl and the mixture was stirred at room temperature forabout 2.5 h. The mixture was concentrated and co-evaporated three timeswith ethanol to give 20 mg of 18D isomer 1. MS (Cl, NH₃) 492 (MH⁺).¹HNMR (CD₃OD): (partial) δ 8.42 (br d, 1H), 7.35 (m, 5H), 7.18 (m, 5H),5.23 (m, 2H), 4.91 (m, 1H), 4.54 (m, 4H), 3.80 (m, 2H), 3.63 (m, 1H),3.12 (m, 1H), 3.07 (m, 3H), 2.61 (m, 3H), 1.62 (m, 6H), 1.39 (m, 1H).

E.2-Amino-N-[2-(3a-(S)-benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramidehydrochloride

To 200 mg (0.34 mmol) of 18C isomer 2 in 20 mL of ethanol was added 10mL of concentrated HCl and the mixture was stirred at room temperaturefor about 2.5 h. The mixture was concentrated and co-evaporated threetimes with ethanol to give 30 mg of 18E isomer 2. MS (Cl, NH₃) 492(MH⁺). ¹HNMR (CD₃OD): (partial) δ 8.29 (br d, 1H), 7.30 (m, 5H), 7.11(m, 4H), 6.88 (m, 1H), 5.29 (m, 1H), 4.92 (m, 1H), 4.62 (m, 3H),3.91-3.70 (m, 3H), 3.22-2.95 (m, 3H), 2.66 (m, 3H), 1.57 (m, 6H), 1.30(m, 1H), 0.89 (m, 1H).

EXAMPLE 192-Amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-3-oxo-3a-(R,S)-thiazol-4-ylmethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-isobutyramidedihydrochloride

A. 4-Oxo-3-(R,S)-thiazol-4-ylmethyl-piperidine-1,3-dicarboxylic acid1-tert-butyl ester 3-ethyl ester

To a solution of 300 mg (1.10 mmol) of 1A in 5 mL of THF at 0° C. wasadded 67 mg (1.66 mmol) of sodium hydride (60% oil dispersion) and themixture was stirred for about 30 min. A solution of 204 mg (1.21 mmol)of 4-chloromethylthiazole (Hsiao, C. N; Synth. Comm. 20, p. 3507 (1990))in 5 mL of THF was added to the cold solution, followed by 87 mg (0.53mmol) of potassium iodide and the mixture was heated at reflux for about17 h. The mixture was diluted with water and extracted with ethylacetate. The combined organic extracts were dried over Na₂SO₄ andconcentrated and the residue was purified by silica gel chromatography(7:3 v/v hexane:ethyl acetate) to give 90 mg of the title compound. MS(Cl, NH₃) 648 (MH⁺).

B.2-Methyl-3-oxo-3a-(R,S)-thiazol-4-ylmethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

To 90 mg (0.24 mmol) of 19A in 2 mL of ethanol was added 11.2 mg (0.24mmol) of methylhydrazine and the mixture was heated at reflux for about17 h. An additional 33.6 mg (0.72 mmol) of methylhydrazine was added andthe mixture was heated at reflux for about 7 h. The mixture wasconcentrated and the residue was dissolved in 3 mL of toluene and heatedat reflux for about 17 h. The mixture was concentrated and the residuewas purified by silica gel chromatography (6:4 v/v hexane:ethyl acetate)to give 44 mg of 19B. MS (Cl, NH₃) 648 (MH⁺).

C.2-Methyl-3a-(R,S)-thiazol-4-ylmethyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-onedihydrochloride

A mixture of 44 mg (0.10 mmol) of 19B in 1 mL of 4M HCl in dioxane wasstirred at room temperature for about 4 h. The mixture was concentratedand co-evaporated with methylene chloride to give 40 mg of 19C. MS (Cl,NH₃) 251 (MH⁺).

D.{1-[1-(R)-Benzyloxymethyl-2-(2-methyl-3-oxo-3a-(R,S)-thiazol-4-ylmethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethylcarbamoyl]-1-methylethyl}-carbamicacid tert-butyl ester

According to the method outlined in General Procedure A, 40 mg (0.12mmol) of 19C and 39 mg (0.12 mmol) of 14F were coupled and the residuewas purified by silica gel chromatography (9:1 v/v ethyl acetate:hexane)to give 40 mg of 19D. MS (Cl, NH₃) 613 (MH⁺).

E.2-Amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-3-oxo-3a-(R,S)-thiazol-4-ylmethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-isobutyramidedihydrochloride

A mixture of 40 mg (0.06 mmol) of 19D in 1 mL of 4M HCl in dioxane wasstirred at room temperature for about 5 h. The mixture was concentratedand co-evaporated with methylene chloride to give 40 mg of 19E. MS (Cl,NH₃) 513 (MH⁺).

EXAMPLE 202-Amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramideL-tartaric acid salt.

To 4.6 g of the title compound of Example 14 in 20 mL of methanol, asolution of 1.36 g of L-tartaric acid in 20 mL of methanol was added atabout 0° C. The mixture was warmed to room temperature, stirred forabout 40 min and concentrated in vacuo. The residue was diluted with 220mL of ethyl acetate, heated at reflux for about 1.5 h, then stirred atabout 72° C. for about 18 h. The mixture was cooled to room temperature,and filtered to give 5.78 g of the title compound as a colorlesscrystalline.

EXAMPLE 213-Benzyl-3-methoxycarbonylmethyl-4-oxo-piperidine-1-carboxylic acidtert-butyl ester

A. 3-Benzyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester

A mixture of the β-ketoester (4480 mg, 12.9 mmol) and LiCl (1100 mg,25.8 mmol) was heated in DMF (2.0 ml) at about 120° C. for about 17 h.The reaction mixture was cooled to room temperature and extracted withEtOAc (3×100 mL). The combined extracts were dried and concentrated invacuo. The crude product was chromatographed on SiO₂ using 20% ethylacetate/hexanes to give 1320 mg of the desired product as a yellow oil.¹H NMR (250 MHz, CDCl₃): d: 7.4 (m, 5H), 4.2 (m, 1H), 3.4 (m, 1H), 3.3(dd, 1H), 3.05 (dd, 1H), 2.7 (m, 1H), 2.55 (m, 4H), 1.5 (s, 9H); MS(APCI): 190 (M+1−BOC).

B. 3-Benzyl-3-methoxycarbonylmethyl-4-oxo-piperidine-1-carboxylic acidtert-butyl ester

A solution of the product from Step A of Example 21 above (1320 mg, 4.56mmol), pyrrolidine (972 mg, 13 mmol) and p-toluenesulfonic acid (33 mg)in benzene (30 ml) was refluxed through 3 molecular sieves for about 17h. The reaction mixture was cooled to room temperature and concentratedin vacuo. The residue was dissolved in benzene (10 ml) and cooled toabout 0° C. Methyl bromoacetate (1530 mg, 10 mmol) was added dropwise.The reaction mixture was slowly allowed to warm to room temperature andthen was heated under reflux for about 17 h at which point H₂O (5 mL)was added. After refluxing for about another 2 h, the reaction mixturewas cooled to room temperature and extracted with EtOAc (3×100 ml). Thecombined organic extracts were dried and concentrated in vacuo. Thecrude residue was chromatographed on SiO₂-gel using 15% ethylacetate/hexanes to give 280 mg of product. ¹H NMR (250 MHz, CDCl₃): d:7.35 (m, 5H), 4.5 (m, 1H), 3.8 (s, 3H), 3.4 (dd, 1H), 3.1 (m, 1H), 2.85(m, 4H), 2.6 (m, 1H), 2.4 (m, 1H), 1.5 (s, 9H); MS (APCI): 362 (M+1).

EXAMPLE 22 6-Oxo-1-phenyl-cyclohexane-1,3-dicarboxylic acid 3-tert-butylester 1-methyl ester

A solution of diphenylmercury (890 mg, 2.5 mmol) in CHCl₃ (4 ml) underN₂ was heated to about 40° C. Lead tetraacetate (1110 mg, 2.5 mmol) wasadded in small portions and the greenish yellow solution was stirred atabout 40° C. for about 0.5 h. The β-ketoester (520 mg, 2.0 mmol) wasthen added, followed by pyridine (0.2 ml, 2.5 mmol). After about 5 h atabout 40° C., the reaction mixture was concentrated in vacuo and theresidue was dissolved in ether (100 ml) and filtered. The filtrate waswashed with 3N H₂SO₄ (3×), dried and concentrated to give 616 mg of ayellow solid. Flash chromatography over SiO₂-gel using 25% ethylacetate/hexanes provided 368 mg of the desired product. ¹H NMR (400 MHz,CDCl₃): d 7.15 (m, 5H), 4.4 (s, 2H), 3.7 (s, 5H), 2.6 (s, 2H), 1.5 (s,9H); MS (APCI): 334 (M+1).

EXAMPLE 23 (D)-2-Amino-3-(2,4-dichloro-benzyloxy)-propionic acidhydrochloride

A. (D)-2-tert-Butoxycarbonylamino-3-(2,4-dichloro-benzyloxy)-propionicacid

To a stirred solution of Boc-D-serine (8.2 g, 40 mmol) in DMF (75 ml) atabout 0° C. was added NaH (60% dispersion, 3.2 g, 80 mmol) over about a10 minute period. The reaction mixture was stirred for about 1.75 h atabout 0° C., then about 0.25 h at room temperature. After cooling toabout 0° C., a solution of 2,4-dichlorotoluene (5.56 ml, 40 mmol) in DMF(5 ml) was added dropwise. The reaction mixture was allowed to warm toabout 23° C. and was stirred for about 17 h, then was partitionedbetween di-isopropylether and 10% HCl. The aqueous solution wasextracted with di-isopropyl ether (2×). The combined extracts werewashed with saturated aqueous brine, dried and concentrated to give14.75 g of crude product which was used without further purification. ¹HNMR (400 MHz, CDCl₃): d 7.6-7.2 (m, 3H), 5.4 (d, 1H), 4.6 (s, 2H), 4.0(d, 1H), 3.8 (dd, 2H), 1.1 (s, 9H); MS (APCI): 246,266 (M+1, M+2).

B. (D)-2-Amino-3-(2,4-dichloro-benzyloxy)-propionic acid hydrochloride

The product from step A of Example 23 above (14.7 g, 40 mmol) wasstirred in 4 M HCl/dioxane (100 ml) for about 17 h. The reaction mixturewas concentrated in vacuo to give 12 g of a pale yellow solid (100%). MS(APCI): 265 (M+1).

EXAMPLE 24

Example 24 having the formula shown below,

wherein R¹ is —CH₂-phenyl and R² is methyl, was synthesized in ananalogous manner to the procedures described in Examples 3C to 3F usingthe title compound of Example 21 as starting material. Both the R,R andS,R diasteromers (* indicates the other stereoisomer center at the C-3carbon of the above structure) were isolated. Mass spec. (M+1)=520; MSmethod=particle bombardment.

EXAMPLES 25 TO 26

Examples 25 and 26 having the formula shown below,

wherein for both examples 25 and 26 R¹ is phenyl and R² is methyl, whereexample 25 is the R,R isomer and example 26 is the S,R isomer. Examples25 and 26 were synthesized in an analogous manner to the proceduresdescribed in Examples 3C to 3F using the title compound of Example 22 asstarting material followed by chromatographic separation of the twoseparate isomers. Mass spec. of each example (M+1)=493, MSmethod=particle bombardment.

EXAMPLES 27-159

Examples 27 to 159 listed in the table below, were prepared according tothe scheme illustrated below by coupling the appropriately substitutedpyrazalone-piperidine of formula I (in the below scheme) with the(D)-OBnSer derivative II (in the below scheme) in an analogous manner tothe procedures described in Examples 3E and 3F.

The pyrazalone-piperidines of formula I were prepared analogouslyaccording to the procedures described in Examples 3B and 3C startingwith the appropriate alkylating agent and alkylhydrazine; the (D)-OBnSerderivatives (II) were prepared in three steps analogously to theprocedures described in Example 23A, Example 23B and Example 5F.

MS Ex. # Isomer R² R¹ = —CH₂—A¹ Ar MS Method  27 d1 H 2-pyridyl phenyl493 PB  28 d1 H 4-thiazolyl phenyl 499 PB  29 d2 H 4-thiazolyl phenyl499 PB  30 d1 H 5-thiazolyl phenyl 499 APCl  31 d1 Me phenyl2,4-di-Cl-Ph 574.5 APCl  32 d1 Me phenyl 2,4-di-F-Ph 542 PB  33 d1 Mephenyl [2,3-O—CH₂—O]Phenyl 550.2 PB  34 d1 Me phenyl 2-CF₃-Ph 575 PB  35d1 Me phenyl 2-Me-Ph 520 PB  36 d1 Me phenyl 2-pyridyl 507 PB  37 d1 Mephenyl 3,4-di-F-Ph 542 PB  38 d1,2 Me phenyl 3,5-di-CF₃-Ph 642 PB  39 d1Me phenyl 3,5-di-Cl-Ph 576 APCl  40 d2 Me phenyl 3-CF₃-Ph 575 APCl  41d1 Me phenyl 3-Cl-Ph 540 APCl  42 d1 Me phenyl 3-Cl-thiophene 546, 548APCl  43 d1 Me phenyl 3-F-4-Cl-Ph 560 APCl  44 d1 Me phenyl 3-Me-Ph 520PB  45 d1 Me phenyl 4-Cl-Ph 540 PB  46 d1 Me phenyl 4-pyridyl 507 PB  47d1 Me phenyl 4-thiazolyl 513 PB  48 d1 Me phenyl 5-thiazolyl 513 APCl 49 d1,2 Me phenyl benzisoxazolyl 547 PB  50 d1 Me phenyl 4-pyrimidinyl508 PB  51 d1,2 Me 4-Ph-Ph 4-thiazolyl 589 APCl  52 d1,2 Me 4-Ph-Ph2-pyridyl 583 APCl  53 d1 Me 4-F-Ph phenyl 524 PB  54 d2 Me 4-F-Phphenyl 524 PB  55 d1 Me 4-F-Ph 3-Cl-Ph 558 PB  56 d2 Me 4-F-Ph 3-Cl-Ph558 PB  57 d1 Me 4-F-Ph 3,4-di-F-Ph 560 APCl  58 d2 Me 4-F-Ph3,4-di-F-Ph 560 APCl  59 d1,2 Me 4-F-Ph 2-pyridyl 525 APCl  60 d1,2 Me4-F-Ph 2-CF₃-Ph 592 APCl  61 d1 Me 4-CF₃-Ph 4-Cl-Ph 609 APCl  62 d1,2 Me4-CF₃-Ph 4-Cl-Ph 609 APCl  63 d1,2 Me 3-pyridyl phenyl 508 PB  64 d1 Me3-phenyl 3-pyridyl 508 PB  65 d1 Me 2-quinolinyl phenyl 594 PB  66 d2 Me2-quinolinyl phenyl 594 PB  67 d1 Me 2-pyridyl phenyl 506 PB  68 d2 Me2-pyridyl phenyl 506 PB  69 d1,2 Me 2-pyridyl 3-F-4-Cl-Ph 559, 561 APCl 70 d1 Me 2-pyridyl 3-Cl-thiophene 547, 549 APCl  71 d1 Me 2-pyridyl3-CF₃-Ph 575 PB  72 d1,2 Me 2,4-di-F-Ph 3,4-di-F-Ph 579 APCl  73 d1,2 Me2,4-di-F-Ph 2-pyridyl 544 PB  74 d1 Me 4-thiazolyl phenyl 513 APCl  75d2 Me 4-thiazolyl phenyl 513 PB  76 d1 Me 5-thiazolyl phenyl 513 PB  77d1 Et 2-pyridyl phenyl 521 PB  78 d1,2 Et phenyl 4-thiazolyl 541 APCl 79 d1 Et phenyl 3,5-di-CF₃-Ph 656 PB  80 d1,2 Et phenyl 3,4-di-F-Ph 556PB  81 d1 Et 2,4-di-F-Ph 2,4-di-F-Ph 593 APCl  82 d2 Et 2,4-di-F-Ph2,4-di-F-Ph 593 APCl  83 d1 Et 2,4-di-F-Ph 2-CF₃-Ph 625 APCl  84 d2 Et2,4-di-F-Ph 2-CF₃-Ph 625 APCl  85 d1 Et 2,4-di-F-Ph 3,4-di-F-Ph 593 APCl 86 d2 Et 2,4-di-F-Ph 3,4-di-F-Ph 593 APCl  87 d1 Et 2-pyridyl3,4-di-F-Ph 607 PB  88 d2 Et 2-pyridyl 3,4-di-F-Ph 607 PB  89 d1 Et4-CF₃-Ph 2.4-di-F-Ph 625 APCl  90 d2 Et 4-CF₃-Ph 2,4-di-F-Ph 625 APCl 91 d1 Et 4-CF₃-Ph 3-Cl-Ph 623 APCl  92 d1 Et 4-CF₃-Ph 4-Cl-Ph 623 APCl 93 d2 Et 4-CF₃-Ph 4-Cl-Ph 623 APCl  94 d1 Et 4-CH₃-Ph 3-Cl-Ph 568 APCl 95 d2 Et 4-CH₃-Ph 3-Cl-Ph 568 APCl  96 d1 Et 4-Cl-Ph 3,4-di-F-Ph 590 PB 97 d2 Et 4-Cl-Ph 3,4-di-F-Ph 590 PB  98 d1 Et 4-Cl-Ph 3-5-di-Cl-Ph 622PB  99 d2 Et 4-Cl-Ph 3-5-di-Cl-Ph 622 PB 100 d1 Et 4-Cl-Ph 3-Cl-Ph 589PB 101 d2 Et 4-Cl-Ph 3-Cl-Ph 589 PB 102 d1 Et 4-F-Ph 3,4-di-F-Ph 574 PB103 d2 Et 4-F-Ph 3,4-di-F-Ph 574 PB 104 d1 Et 4-F-Ph 3-Cl-Ph 572 APCl105 d2 Et 4-F-Ph 3-Cl-Ph 572 APCl 106 d1,2 Et 4-Me-Ph 2-CF₃-Ph 602 APCl107 d1,2 Et 4-Me-Ph 3,4-di-F-Ph 570 APCl 108 d1,2 CF₃CH₂ phenyl4-thiazolyl 595 APCl 109 d1 CF₃CH₂ phenyl 3-CF₃-Ph 642.3 APCl 110 d1CF₃CH₂ phenyl 3,5-di-Cl-Ph 643 APCl 111 d2 CF₃CH₂ phenyl 3,5-di-Cl-Ph644 APCl 112 d1 CF₃CH₂ phenyl 3,4-di-F-Ph 610.2 APCl 113 d2 CF₃CH₂phenyl 3,4-di-F-Ph 610.2 APCl 114 d1 CF₃CH₂ phenyl 3,5-di-Cl-Ph 643 APCl115 d2 CF₃CH₂ phenyl 3,5-di-Cl-Ph 644 APCl 116 d1 CF₃CH₂ phenyl 3-CF₃-Ph642.3 APCl 117 d1 CF₃CH₂ phenyl 3,4-di-F-Ph 610.2 APCl 118 d2 CF₃CH₂phenyl 3,4-di-F-Ph 610.2 APCl 119 d1,2 CF₃CH₂ phenyl 4-thiazolyl 595APCl 120 d1,2 CF₃CH₂ 2,4-di-Cl-Ph 2-pyridyl 643 APCl 121 d1,2 CF₃CH₂2,4-di-Cl-Ph 4-thiazolyl 649 APCl 122 d1 CF₃CH₂ 2,4-F-Ph 2-CF₃-Ph 679APCl 123 d2 CF₃CH₂ 2,4-F-Ph 2-CF₃-Ph 679 APCl 124 d1 CF₃CH₂ 2,4-F-Ph3,4-di-F-Ph 647 APCl 125 d2 CF₃CH₂ 2,4-F-Ph 3,4-di-F-Ph 647 APCl 126d1,2 CF₃CH₂ 2,4-F-Ph 4-thiazolyl 617 PB 127 d1 CF₃CH₂ 2-pyridyl2,4-di-Cl-Ph 643 APCl 128 d2 CF₃CH₂ 2-pyridyl 2,4-di-Cl-Ph 643 APCl 129d1 CF₃CH₂ 2-pyridyl 2,4-di-F-Ph 611 PB 130 d2 CF₃CH₂ 2-pyridyl2,4-di-F-Ph 611 PB 131 d1 CF₃CH₂ 2-pyridyl 2-CF₃-4-F-Ph 661 APCl 132 d1CF₃CH₂ 2-pyridyl 2-CF₃-Ph 643 PB 133 d2 CF₃CH₂ 2-pyridyl 2-CF₃-Ph 643 PB134 d1 CF₃CH₂ 2-pyridyl 3,4-di-F-Ph 611 PB 135 d2 CF₃CH₂ 2-pyridyl3,4-di-F-Ph 611 PB 136 d1 CF₃CH₂ 2-pyridyl 3,5-di-Cl-Ph 643 APCl 137 d1CF₃CH₂ 2-pyridyl 3-Cl-Ph 609 PB 138 d1 CF₃CH₂ 2-pyridyl 3-Cl-thiophene615, 617 APCl 139 d1,2 CF₃CH₂ 2-pyridyl 3-F-4-Cl-Ph 627, 629 APCl 140 d1CF₃CH₂ 2-pyridyl 3-OCF₃-Ph 659 APCl 141 d1 CF₃CH₂ 2-pyridyl 4-Cl-Ph 609PB 142 d2 CF₃CH₂ 2-pyridyl 4-Cl-Ph 609 PB 143 d1,2 CF₃CH₂ 3-pyridyl2,4-di-F-Ph 612 APCl 144 d1,2 CF₃CH₂ 3-pyridyl 2-CF₃-Ph 644 APCl 145d1,2 CF₃CH₂ 3-pyridyl 4-Cl-Ph 610 APCl 146 d1 CF₃CH₂ 4-CH₃-Ph 3-Cl-Ph622 APCl 147 d2 CF₃CH₂ 4-CH₃-Ph 3-Cl-Ph 622 APCl 148 d1 CF₃CH₂ 4-Cl-Ph3,4-di-F-Ph 644 PB 149 d2 CF₃CH₂ 4-Cl-Ph 3,4-di-F-Ph 644 PB 150 d1CF₃CH₂ 4-Cl-Ph 3,5-di-Cl-Ph 675 PB 151 d2 CF₃CH₂ 4-Cl-Ph 3,5-di-Cl-Ph675 PB 152 d2 CF₃CH₂ 4-Cl-Ph 3-Cl-Ph 642 PB 153 d1 CF₃CH₂ 4-Cl-Ph3-Cl-Ph 642 PB 154 d1 CF₃CH₂ 4-F-Ph 3,4-di-F-Ph 628 PB 155 d2 CF₃CH₂4-F-Ph 3,4-di-F-Ph 628 PB 156 d1 CF₃CH₂ 4-F-Ph 3-Cl-Ph 626 PB 157 d2CF₃CH₂ 4-F-Ph 3-Cl-Ph 626 PB 158 d1,2 CF₃CH₂ 4-Me-Ph 2-CF₃-Ph 656 APCl159 d1,2 CF₃CH₂ 4-Me-Ph 3,4-di-F-Ph 624 APCl Note: in the above table,the isomer designation refers to the stereochemistry at the C-3 position#(indicated by the “*” in the structure) of the pyrazalone-piperidinegroup; d1 and d2 refer to isomers that were chromatographicallyseparated; d1,2 refers to a # mixture of isomers. Abbreviations used inthe table above are: Ph is phenyl; PB is particle bombardment; and APClis atmospheric pressure chemical ionization. The following are NMR datafor the compounds of the above table as indicated.

EXAMPLE 37

¹H NMR (400 MHz, d4-MeOH): d 7.2 (m, 5H), 5.2 (t, 1H), 4.6 (m, 3H), 3.8(d, 2H), 3.1 (d, 1H), 3.0 (s, 3H), 2.6 (dd, 2H), 1.6 (s, 6H).

EXAMPLES 67 & 68

¹H NMR (300 MHz, d4-MeOH): d 8.85 (s, 1H), 8.6 (t, 1H), 8.1 (d, 1H), 8.0(t, 1H), 7.35 (s, 5H), 5.15 (s, 1H), 4.6 (bs, 3H), 3.85 (m, 2H), 3.65(m, 2H), 3.2 (s, 3H), 2.75 (m, 2H), 1.65 (s, 6H).

EXAMPLE 128

¹H NMR (400 MHz, d4-MeOH): d 8.8 (s, 1H), 8.6 (s, 1H), 8.5 (t, 1H), 7.96(t, 1H), 7.9 (d, 1H), 7.45 (d, 1H), 7.33 (d, 1H), 5.2 (s, 1H), 4.6 (s,3H), 4.4 (m, 1H), 4.2 (m, 2H), 3.9 (m, 4H), 3.5 (m), 3.2 (m, 2H), 2.8(dd, 2H), 1.6 (s, 6H).

EXAMPLES 129 & 130

¹H NMR (400 MHz, d4-MeOH): d 8.76 (s, 1H), 8.50 (t, 1H), 7.92 (dt, 2H),7.43 (q, 1H), 6.90 (t, 1H), 5.20 (m, 1H), 4.90 (m), 4.30 (m, 1H), 4.20(m, 1H), 3.7−3.4 (m), 3.30 (s, 2H), 3.20 (m, 1H), 2.80 (dd, 2H), 1.60(s, 6H).

EXAMPLE 137

¹H NMR (300 MHz, d4-MeOH): d 8.7 (1, 1H), 8.45 (t, 1 H), 7.9 (t, 2 H),7.25 (m, 4 H), 5.2 (m, 1 H), 4.95 (d, 1 H), 4.6 (s, 2H), 4.3 (m, 1 H),3.8 (t, 2H), 3.5 (dd, 2 H), 2.8 (m, 1H), 2.8 (dd, 2 H), 1.6 (s, 6 H).

EXAMPLE 138

¹H NMR (400 MHz, d4-MeOH): d 8.8 (dd, 1H), 8.6 (s, 1H), 8.5 (t, 1H),7.95 (t, 1H), 7.9 (s, 1H), 7.3 (s, 1H), 7.0 (s, 1H), 5.2 (s, 1H), 4.85(s, 3H), 4.4 (m, 1H), 4.18 (m, 1H), 3.8 (m, 2H), 3.5 (dd, 2H), 3.2 (d,2H), 2.8 (dd, 2H), 1.6 (s, 6H).

EXAMPLES 141 & 142

¹H NMR (300 MHz, d4-MeOH): d 8.75 (m, 1 H), 8.5 (m, 1 H), 7.9 (m, 2 H),7.3 (s, 2 H), 5.2 (m, 1 H), 4.65 (m, 1 H), 4.55 (s, 2 H), 4.35 (m, 1 H),4.20 (m, 1 H), 3.8 (t, 1 H), 3.5 (dd, 2 H), 3.15 (d, 1 H), 2.8 (dd, 2H), 1.6 (s, 2 H).

EXAMPLES 160-179

Examples 160 to 179 shown in the table below were prepared according tothe scheme illustrated below by coupling the appropriately substitutedpyrazalone-piperidine (I) (in the scheme) with the (D)-Trp derivative(III) (see Example 2C) in an analogous manner to the proceduresdescribed in Examples 3E and 3F.

Ex. # Isomer R² R¹ = —CH₂—A¹ MS MS Method 160 d1 Me 4-CF₃-Ph 584 APCl161 d1,2 Me 4-CF₃-Ph 584 APCl 162 d1 Me 4-F-Ph 533 PB 163 d2 Me 4-F-Ph533 PB 164 d1 Me 4-Ph-Ph 591 APCl 165 d1,2 Et 2,4-di-Cl-Ph 597 APCl 166d1,2 Et 2,4-F-Ph 566 APCl 167 d1 Et 4-CF₃-Ph 598 APCl 168 d1,2 Et4-CF₃-Ph 598 APCl 169 d1 Et 4-Cl-Ph 563 PB 170 d2 Et 4-Cl-Ph 563 PB 171d1,2 Et 4-F-Ph 547 APCl 172 d1,2 Et 4-Me-Ph 543 APCl 173 d1,2 CF₃CH₂2,4-di-Cl-Ph 651.5 APCl 174 d1,2 CF₃CH₂ 2,4-di-F-Ph 620 APCl 175 d1CF₃CH₂ 4-Cl-Ph 617 PB 176 d2 CF₃CH₂ 4-Cl-Ph 617 PB 177 d1 CF₃CH₂ 4-F-Ph601 APCl 178 d2 CF₃CH₂ 4-F-Ph 601 APCl 179 d1,2 CF₃CH₂ 4-Me-Ph 597 APClNote: in the above table, the isomer designation refers to thestereochemistry at the C-3 position (indicated by the “*” in thestructure) of the pyrazalone-piperidine group; d1 and d2 refer toisomers that were chromatographically separated; d1,2 refers to amixture of isomers.

EXAMPLES 180-183

Examples 180 to 183 shown in the table below were prepared according tothe scheme illustrated below by coupling the appropriately substitutedpyrazalone-piperidine I with the acid intermediate IV in an analogousmanner to the procedures described in Examples 3E and 3F.

The acid intermediate (IV) was prepared by treating an amino acid withthe product from Example 5D using the established procedure described inExample 5F.

Iso- Ex. # mer R² R¹ = —CH₂—A¹ Ar MS Method 180 d1,2 Me Phenyl (CH₂)₂Ph504 PB 181 d1,2 Me Phenyl SCH₂Ph 559 PB 182 d1 Me Phenyl 2-Naphthalenyl527 APCl 183 d1,2 Me Phenyl CH₂O-(4-F-Ph) 524 PB Note: in the abovetable, the isomer designation refers to the stereochemistry at the C-3position (indicated by the “*” in the structure) of thepyrazalone-piperidine group; d1 and d2 refer to isomers that werechromatographically separated; d1,2 refers to a mixture of isomers.

What is claimed is:
 1. A compound of the formula

the racemic-diastereomeric mixtures and optical isomers of saidcompounds and the pharmaceutically-acceptable salts thereof, wherein eis 0; n is 0 and w is 1, or n is 1 and w is 0; R¹ is hydrogen, —CN,—(CH₂)_(q)N(X⁶)C(O)X⁶, —(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)-A¹,—(CH₂)_(q)N(X⁶)SO₂(CH₂)_(t)-A¹, —(CH₂)_(q)N(X⁶)SO₂X⁶,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)-A¹, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)-A¹,—(CH₂)_(q)C(O)OX⁶, —(CH₂)_(q)C(O)O(CH₂)_(t)-A¹, —(CH₂)_(q)OX⁶,—(CH₂)_(q)OC(O)X⁶, —(CH₂)_(q)OC(O)(CH₂)_(t)-A¹,—(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)-A¹, —(CH₂)_(q)OC(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)-A¹, —(CH₂)_(q)N(X⁶)C(O)OX⁶,—(CH₂)_(q)N(X⁶)SO₂N(X⁶)(X⁶), —(CH₂)_(q)S(O)_(m)X⁶,—(CH₂)_(q)S(O)_(m)(CH₂)_(t)-A¹, —(C₁-C₁₀)alkyl, —(CH₂)_(t)-A¹,—(CH₂)_(q)—(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹—(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)-A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)—(C₃-C₇)cycloalkyl;where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxyl, (C₁-C₄)alkoxy,carboxyl, CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl, 1H-tetrazol-5-yl or 1 to 3 fluoro; Y¹ is O, S(O)_(m), —C(O)NX⁶, —CH═CH—,—C≡C—, —N(X⁶)C(O)—, —C(O)NX⁶—, —C(O)O—, —OC(O)N(X⁶)— or —OC(O)—; q is 0,1, 2, 3 or 4; t is 0, 1, 2 or 3; said (CH₂)_(q) group and (CH₂)_(t)group may each be optionally substituted with 1 to 3 fluoro, 1 or 2(C₁-C₄)alkyl, hydroxyl, (C₁-C₄)alkoxy, carboxyl, —CONH₂,—S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester, or 1 H-tetrazol-5-yl; R²is hydrogen, (C₁-C₈)alkyl, —(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl,—(C₁-C₄)alkyl-A¹ or A¹; where the alkyl groups and the cycloalkyl groupsin the definition of R² are optionally substituted by hydroxyl,—C(O)OX⁶, —C(O)N(X⁶)(X⁶), —N(X⁶)(X⁶), —S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹,—C(O)(X⁶), CF₃, CN or 1 to 3 halogen; A¹ for each occurrence isindependently (C₅-C₇)cycloalkenyl, phenyl or a partially saturated,fully saturated or fully unsaturated 4- to 8-membered ring optionallyhaving 1 to 4 heteroatoms independently selected from the groupconsisting of oxygen, sulfur and nitrogen, or a bicyclic ring systemconsisting of a partially saturated, fully unsaturated or fullysaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen, fused to a partially saturated, fully saturated or fullyunsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen; A¹ for each occurrence is independently optionally substituted,in one or optionally both rings if A¹ is a bicyclic ring system, with upto three substituents, each substituent independently selected from thegroup consisting of F, Cl, Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶,—C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo, (C₁-C₆)alkyl, nitro, cyano, benzyl,—S(O)_(m)(C₁-C₆)alkyl, 1 H-tetrazol-5-yl, phenyl, phenoxy,phenylalkyloxy, halophenyl, methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶),—SO₂N(X⁶)(X⁶), —N(X⁶)SO₂-phenyl, —N(X⁶)SO₂X⁶, —CONX¹¹X¹², —SO₂NX¹¹X¹²,—NX⁶SO₂X¹², —NX⁶CONX¹¹X¹², —NX⁶SO₂NX¹¹X¹², —NX⁶C(O)X¹², imidazolyl,thiazolyl and tetrazolyl, provided that if A¹ is optionally substitutedwith methylenedioxy then it can only be substituted by onemethylenedioxy; where X¹¹ is hydrogen or optionally substituted(C₁-C₆)alkyl; the optionally substituted (C₁-C₆)alkyl defined for X¹¹ isoptionally independently substituted with phenyl, phenoxy,(C₁-C₆)alkoxycarbonyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1 to 3hydroxy, 1 to 3 (C₁-C₁₀)alkanoyloxy or 1 to 3 (C₁-C₆)alkoxy; X¹² ishydrogen, (C₁-C₆)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl,provided that when X¹² is not hydrogen, X¹² is optionally substitutedwith one to three substituents independently selected from the groupconsisting of Cl, F, CH₃, OCH₃, OCF₃ and CF₃; or X¹¹ and X¹² are takentogether to form —(CH₂)_(r)-L¹-(CH₂)_(r)—; L¹ is C(X²)(X²), O, S(O)_(m)or N(X²); r for each occurrence is independently 1, 2 or 3; X² for eachoccurrence is independently hydrogen, optionally substituted(C₁-C₆)alkyl, or optionally substituted (C₃-C₇)cycloalkyl, where theoptionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl in the definition of X² are optionally independentlysubstituted with —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halogens or 1to 3 OX³; X³ for each occurrence is independently hydrogen or(C₁-C₆)alkyl; X⁶ for each occurence is independently hydrogen,optionally substituted (C₁-C₆)alkyl, (C₂-C₆)halogenated alkyl,optionally substituted (C₃-C₇)cycloalkyl, (C₃-C₇)-halogenatedcycloalkyl,where optionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl in the definition of X⁶ is optionally independentlysubstituted with, hydroxyl, (C₁-C₄)alkoxy, carboxyl, CONH₂,—S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl, 1 H-tetrazol-5-yl or 1 or 2(C₁-C₄)alkyl; or where there are two X⁶ groups on one atom and both X⁶are (C₁-C₆)alkyl, the two (C₁-C₆)alkyl groups may be optionally joinedand, together with the atom to which the two X⁶ groups are attached,form a 4- to 9-membered ring optionally having oxygen, sulfur or NX⁷; X⁷is hydrogen or (C₁-C₆)alkyl optionally substituted with hydroxyl; and mfor each occurrence is independently 0, 1 or 2; with the proviso that:X⁶ and X¹² cannot be hydrogen when it is attached to C(O) or SO₂ in theform C(O)X⁶, C(O)X¹², SO₂X⁶ or SO₂X¹²; and when R² is hydrogen then R¹is not —CH═CH-phenyl.
 2. A compound according to claim 1 wherein w is 0;n is 1; R¹ is hydrogen, —(CH₂)_(q)—(C₃-C₇)cycloalkyl, —(CH₂)_(t)-A¹ or(C₁-C₁₀)alkyl where the (C₁-C₁₀)alkyl and (C₃-C₇)cycloalkyl groups areoptionally substituted with 1 to 3 fluoro and A¹ in the definition of R¹is optionally substituted with 1 to 3 substituents independentlyselected from the group consisting of F, Cl, Me, methoxy, CF₃, OCF₃ andOCF₂H; R² is hydrogen, (C₁-C₈)alkyl-(C₃-C₇)cycloalkyl, phenyl, or(C₁-C₃)alkyl-phenyl where the alkyl and phenyl groups are optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of F, CF₃, OH and methoxy.
 3. A compound of the formula

the racemic-diastereomeric mixtures and optical isomers of saidcompounds, wherein Z¹⁰⁰ is methyl, BOC, CBZ, CF₃C(O)—, FMOC, TROC,trityl, tosyl, CH₃C(O)— or optionally substituted benzyl whichoptionally substituted with methoxy, dimethoxy or nitro; e is 0; n is 0and w is 1, or n is 1 and w is 0; R¹ is hydrogen, —CN,—(CH₂)_(q)N(X⁶)C(O)X⁶, —(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)-A¹,—(CH₂)_(q)N(X⁶)SO₂(CH₂)_(t)-A¹, —(CH₂)_(q)N(X⁶)SO₂X⁶,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)-A¹, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)-A¹,—(CH₂)_(q)C(O)OX⁶, —(CH₂)_(q)C(O)O(CH₂)_(t)-A¹, —(CH₂)_(q)OX⁶,—(CH₂)_(q)OC(O)X⁶, —(CH₂)_(q)OC(O)(CH₂)_(t)-A¹,—(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)-A¹, —(CH₂)_(q)OC(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)-A¹, —(CH₂)_(q)N(X⁶)C(O)OX⁶,—(CH₂)_(q)N(X⁶)SO₂N(X⁶)(X⁶), —(CH₂)_(q)S(O)_(m)X⁶,—(CH₂)_(q)S(O)_(m)(CH₂)_(t)-A¹, —(C₁-C₁₀)alkyl, —(CH₂)_(t)-A¹,—(CH₂)_(q)—(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹—(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)-A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)—(C₃-C₇)cycloalkyl;where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxyl, (C₁-C₄)alkoxy,carboxyl, CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl, 1H-tetrazol-5-yl or 1 to 3 fluoro; Y¹ is O, S(O)_(m), —C(O)NX⁶, —CH═CH—,—C≡C—, —N(X⁶)C(O), —C(O)NX⁶, —C(O)O, —OC(O)N(X⁶) or —OC(O); q is 0, 1,2, 3 or 4; t is 0, 1, 2 or 3; said (CH₂)_(q) group and (CH₂)_(t) groupmay each be optionally substituted with hydroxyl, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl, 1H-tetrazol-5-yl, 1 to 3 fluoro or 1 or 2 (C₁-C₄)alkyl; R² is hydrogen,(C₁-C₈)alkyl, —(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl, —(C₁-C₄)alkyl-A¹ or A¹;where the alkyl groups and the cycloalkyl groups in the definition of R²are optionally substituted with hydroxyl, —C(O)OX⁶, —C(O)N(X⁶)(X⁶),—N(X⁶)(X⁶), —S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹, —C(O)(X⁶), CF₃, CN or 1 to 3halogen; A¹ for each occurrence is independently (C₅-C₇)cycloalkenyl,phenyl or a partially saturated, fully saturated or fully unsaturated 4-to 8-membered ring optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of oxygen, sulfur and nitrogen, or abicyclic ring system consisting of a partially saturated, fullyunsaturated or fully saturated 5- or 6-membered ring, optionally having1 to 4 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen, fused to a partially saturated, fullysaturated or fully unsaturated 5- or 6-membered ring, optionally having1 to 4 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen; A¹ for each occurrence is independentlyoptionally substituted, in one or optionally both rings if A¹ is abicyclic ring system, with up to three substituents, each substituentindependently selected from the group consisting of F, Cl, Br, I, OCF₃,OCF₂H, CF₃, CH₃, OCH₃, —OX⁶, —C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo,(C₁-C₆)alkyl, nitro, cyano, benzyl, —S(O)_(m)(C₁-C₆)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl,methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶), —SO₂N(X⁶)(X⁶),—N(X⁶)SO₂-phenyl, —N(X⁶)SO₂X⁶, —CONX¹¹X¹², —SO₂NX¹¹X¹², —NX⁶SO₂X¹²,—NX⁶CONX¹¹X¹², —NX⁶SO₂NX¹¹X¹², —NX⁶C(O)X¹², imidazolyl, thiazolyl andtetrazolyl, provided that if A¹ is optionally substituted withmethylenedioxy then it can only be substituted with one methylenedioxy;where X¹¹ is hydrogen or optionally substituted (C₁-C₆)alkyl; theoptionally substituted (C₁-C₆)alkyl defined for X¹¹ is optionallyindependently substituted with phenyl, phenoxy, (C₁-C₆)alkoxycarbonyl,—S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3(C₁-C₁₀)alkanoyloxy or 1 to 3 (C₁-C₆)alkoxy; X¹² is hydrogen,(C₁-C₆)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, providedthat when X¹² is not hydrogen, X¹² is optionally substituted with one tothree substituents independently selected from the group consisting ofCl, F, CH₃, OCH₃, OCF₃ and CF₃; or X¹¹ and X¹² are taken together toform —(CH₂)_(r)-L¹-(CH₂)_(r)—; L¹ is C(X²)(X²), O, S(O)_(m) or N(X²); rfor each occurrence is independently 1, 2 or 3; X² for each occurrenceis independently hydrogen, optionally substituted (C₁-C₆)alkyl, oroptionally substituted (C₃-C₇)cycloalkyl, where the optionallysubstituted (C₁-C₆)alkyl and optionally substituted (C₃-C₇)cycloalkyl inthe definition of X² are optionally independently substituted with—S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halogens or 1 to 3 OX³; X³ foreach occurrence is independently hydrogen or (C₁-C₆)alkyl; X⁶ for eachoccurrence is independently hydrogen, optionally substituted(C₁-C₆)alkyl, (C₂-C₆)halogenated alkyl, optionally substituted(C₃-C₇)cycloalkyl, (C₃-C₇)-halogenatedcycloalkly, where optionallysubstituted (C₁-C₆)alkyl and optionally substituted (C₃-C₇)cycloalkyl inthe definition of X⁶ is optionally independently substituted withhydroxyl, (C₁-C₄)alkoxy, carboxyl, CONH₂, —S(O)_(m)(C₁-C₆)alkyl,—CO₂(C₁-C₄)alkyl, 1 H-tetrazol-5-yl or 1 or 2 (C₁-C₄)alkyl, or wherethere are two X⁶ groups on one atom and both X⁶ are (C₁-C₆)alkyl, thetwo (C₁-C₆)alkyl groups may be optionally joined and, together with theatom to which the two X⁶ groups are attached, form a 4- to 9-memberedring optionally having oxygen, sulfur or NX⁷; X⁷ is hydrogen or(C₁-C₆)alkyl optionally substituted with hydroxyl; and m for eachoccurrence is independently 0, 1 or 2; with the proviso that: when R²and R¹ are H, then Z¹⁰⁰ is not BOC or benzyl; X⁶ and X¹² cannot behydrogen when it is attached to C(O) or SO₂ in the form C(O)X⁶, C(O)X¹²,SO₂X⁶ or SO₂X¹²; when R² is hydrogen then R¹ is not —CH═CH-phenyl; R² isH and R¹ is —CH₂—CH═CH-Ph, then Z¹⁰⁰ is not BOC; R² is H and R¹ is2-cyclohex-1-enyl then Z¹⁰⁰ is not BOC; R² is H and R¹ is—CH₂—C(CH₃)═CH₂, then Z¹⁰⁰ is not BOC; and R² is phenyl and R¹ is —CH₃,then Z¹⁰⁰ is not CH₃C(O)—.
 4. A compound according to claim 3 wherein wis 0; n is 1; Z¹⁰⁰ is BOC, methyl, benzyl or CBZ; R¹ is hydrogen,—(CH₂)_(q)—(C₃-C₇)cycloalkyl, —(CH₂)_(t)-A¹ or (C₁-C₁₀)alkyl where the(C₁-C₁₀)alkyl and (C₃-C₇)cycloalkyl groups are optionally substitutedwith 1 to 3 fluoro and A¹ in the definition of R¹ is optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of F, Cl, Me, OMe, CF₃, OCF₃ and OCF₂H; R² is hydrogen,(C₁-C₈)alkyl, —(C₀-C₃)alkyl-(C₃-C₇)cycloalkyl, phenyl, or—(C₁-C₃)alkyl-phenyl where the alkyl and phenyl groups are optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of F, CF₃, OM and Ome.
 5. A compound of the formula

the racemic-diastereomeric mixtures and optical isomers of saidcompounds, wherein Z²⁰⁰ is t-BOC, CBZ, CF₃C(O)—, FMOC, TROC, trityl,tosyl or optionally substituted benzyl which is optionally substitutedwith methoxy, dimethoxy or nitro; e is 0; n is 0 and w is 1, or n is 1and w is 0; Y is oxygen or sulfur; R¹ is hydrogen, —CN,—(CH₂)_(q)N(X⁶)C(O)X⁶, —(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)-A¹,—(CH₂)_(q)N(X⁶)SO₂(CH₂)_(t)-A¹, —(CH₂)_(q)N(X⁶)SO₂X⁶,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)-A¹, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)-A¹,—(CH₂)_(q)C(O)OX⁶, —(CH₂)_(q)C(O)O(CH₂)_(t)-A¹, —(CH₂)_(q)OX⁶,—(CH₂)_(q)OC(O)X⁶, —(CH₂)_(q)OC(O)(CH₂)_(t)-A¹,—(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)-A¹, —(CH₂)_(q)OC(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)-A¹, —(CH₂)_(q)N(X⁶)C(O)OX⁶,—(CH₂)_(q)N(X⁶)SO₂N(X⁶)(X⁶), —(CH₂)_(q)S(O)_(m)X⁶,—(CH₂)_(q)S(O)_(m)(CH₂)_(t)-A¹, —(C₁-C₁₀)alkyl, —(CH₂)_(t)-A¹,—(CH₂)_(q)—(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹—(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)-A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)—(C₃-C₇)cycloalkyl;where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxyl, (C₁-C₄)alkoxy,carboxyl, CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester, 1H-tetrazol-5-yl or 1 to 3 fluoro; Y¹ is O, S(O)_(m), —C(O)NX⁶, —CH═CH—,—C≡C—, —N(X⁶)C(O), —C(O)NX⁶, —C(O)O, —OC(O)N(X⁶) or —OC(O); q is 0, 1,2, 3 or 4; t is 0, 1, 2 or 3; said (CH₂)_(q) group and (CH₂)_(t) groupmay each be optionally substituted with hydroxyl, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl, 1H-tetrazol-5-yl, 1 to 3 fluoro or 1 or 2 (C₁-C₄)alkyl; R² is hydrogen,(C₁-C₈)alkyl, —(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl, —(C₁-C₄)alkyl-A¹ or A¹;where the alkyl groups and the cycloalkyl groups in the definition of R²are optionally substituted with hydroxyl, —C(O)OX⁶, —C(O)N(X⁶)(X⁶),—N(X⁶)(X⁶), —S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹, —C(O)(X⁶), CF₃, CN or 1 to 3halogen; R³ is A¹, (C₁-C₁₀)alkyl, —(C₁-C₆)alkyl-A¹,—(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl, —(C₁-C₅)alkyl-X¹—(C₁-C₅)alkyl,—(C₁-C₅)alkyl-X¹—(C₀-C₅)alkyl-A¹ or—(C₁-C₅)alkyl-X¹—(C₁-C₅)alkyl-(C₃-C₇)cycloalkyl; where the alkyl groupsin the definition of R³ is optionally substituted with—S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halogens or 1 to 3 OX³; X¹ is O,S(O)_(m), —N(X²)C(O)—, —C(O)N(X²)—, —OC(O)—, —C(O)O—, —CX²═CX²—,—N(X²)C(O)O—, —OC(O)N(X²)— or —C≡C—, R⁴ is hydrogen, (C₁-C₆)alkyl or(C₃-C₇)cycloalkyl; X⁴ is hydrogen or (C₁-C₆)alkyl or X⁴ is takentogether with R⁴ and the nitrogen atom to which X⁴ is attached and thecarbon atom to which R⁴ is attached and form a five to seven memberedring; R⁶ is

where a and b are independently 0, 1, 2 or 3; X⁵ and X^(5a) are eachindependently selected from the group consisting of hydrogen,trifluoromethyl, A¹ and optionally substituted (C₁-C₆)alkyl; theoptionally substituted (C₁-C₆)alkyl in the definition of X⁵ and X^(5a)is optionally substituted with a substituent selected from the groupconsisting of A¹, —OX², —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX²,(C₃-C₇)cycloalkyl, —N(X²)(X²) and —C(O)N(X²)(X²); Z¹ is a bond, O orN—X², provided that when a and b are both 0 then Z¹ is not N—X² or O;R^(b) is hydrogen or optionally substituted (C₁-C₆)alkyl; where theoptionally substituted (C₁-C₆)alkyl in the definition of R⁸ isoptionally independently substituted with A¹, —C(O)O—(C₁-C₆)alkyl,—S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3—O—C(O)(C₁-C₁₀)alkyl or 1 to 3 (C₁-C₆)alkoxy; or A¹ for each occurrenceis independently (C₅-C₇)cycloalkenyl, phenyl or a partially saturated,fully saturated or fully unsaturated 4- to 8-membered ring optionallyhaving 1 to 4 heteroatoms independently selected from the groupconsisting of oxygen, sulfur and nitrogen, or a bicyclic ring systemconsisting of a partially saturated, fully unsaturated or fullysaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen, fused to a partially saturated, fully saturated or fullyunsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen; A¹ for each occurrence is independently optionally substituted,in one or optionally both rings if A¹ is a bicyclic ring system, with upto three substituents, each substituent independently selected from thegroup consisting of F, Cl, Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶,—C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo, (C₁-C₆)alkyl, nitro, cyano, benzyl,—S(O)_(m)(C₁-C₆)alkyl, 1 H-tetrazol-5-yl, phenyl, phenoxy,phenylalkyloxy, halophenyl, methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶),—SO₂N(X⁶)(X⁶), —N(X⁶)SO₂-phenyl, —N(X⁶)SO₂X⁶, —CONX¹¹X¹², —SO₂NX¹¹X¹²,—NX⁶SO₂X¹², —NX⁶CONX¹¹X¹², —NX⁶SO₂NX¹¹X¹², —NX⁶C(O)X¹², imidazolyl,thiazolyl and tetrazolyl, provided that if A¹ is optionally substitutedwith methylenedioxy then it can only be substituted by onemethylenedioxy; where X¹¹ is hydrogen or optionally substituted(C₁-C₆)alkyl; the optionally substituted (C₁-C₆)alkyl defined for X¹¹ isoptionally independently substituted with phenyl, phenoxy,(C₁-C₆)alkoxycarbonyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1 to 3hydroxy, 1 to 3 (C₁-C₁₀)alkanoyloxy or 1 to 3 (C₁-C₆)alkoxy; X¹² ishydrogen, (C₁-C₆)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl,provided that when X¹² is not hydrogen, X¹² is optionally substitutedwith one to three substituents independently selected from the groupconsisting of Cl, F, CH₃, OCH₃, OCF₃ and CF₃; or X¹¹ and X¹² are takentogether to form —(CH₂)_(r)-L¹-(CH₂)_(r)—; L¹ is C(X²)(X²), O, S(O)_(m)or N(X²); r for each occurrence is independently 1, 2 or 3; X² for eachoccurrence is independently hydrogen, optionally substituted(C₁-C₆)alkyl, or optionally substituted (C₃-C₇)cycloalkyl, where theoptionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl in the definition of X² are optionally independentlysubstituted with, —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halogens or 1to 3 —OX³; X³ for each occurrence is independently hydrogen or(C₁-C₆)alkyl; X⁶ for each occurence is independently hydrogen,optionally substituted (C₁-C₆)alkyl, (C₂-C₆)halogenated alkyl,optionally substituted (C₃-C₇)cycloalkyl, (C₃-C₇)-halogenatedcycloalkyl,where optionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl in the definition of X⁶ is optionally independentlysubstituted with hydroxyl, (C₁-C₄)alkoxy, carboxyl, CONH₂,—S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl, 1 H-tetrazol-5-yl or 1 or 2(C₁-C₄)alkyl; or where there are two X⁶ groups on one atom and both X⁶are (C₁-C₆)alkyl, the two (C₁-C₆)alkyl groups may be optionally joinedand, together with the atom to which the two X⁶ groups are attached,form a 4- to 9-membered ring optionally having oxygen, sulfur or NX⁷; X⁷is hydrogen or (C₁-C₆)alkyl optionally substituted by hydroxyl; and mfor each occurrence is independently 0, 1 or 2; with the proviso that:X⁶ and X¹² cannot be hydrogen when it is attached to C(O) or SO₂ in theform C(O)X⁶, C(O)X¹², SO₂X⁶ or SO₂X¹²; and when R⁶ is a bond then L isN(X²) and each r in the definition —(CH₂)_(r)-L-(CH₂)_(r)— is 2 or 3.